jci.org/this-month

CD8+ T cells in cerebral malaria pathogenesis 3

Postranslational modifications influence prion protein aggregation 4

Reversibility of cardiovascular abnormalities in Cantu syndrome 4

IL-36γ promotes EGFR inhibitor–driven skin toxicity 5

JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight

Scan for the digital version of JCI This Month.

March 2020

This Month

Restoring antitumor immune response in colorectal tumors p. 2

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0ii

Journal of Clinical Investigation Consulting Editors

Soman N. Abraham

John S. Adams

Qais Al-Awqati

Kari Alitalo

Dario C. Altieri

Masayuki Amagai

Brian H. Annex

M. Amin Arnaout

Alan Attie

Jane E. Aubin

Michael F. Beers

Vann Bennett

Gregory K. Bergey

Nina Bhardwaj

Morris J. Birnbaum

Joyce Bischoff

Craig Blackstone

Bruce R. Blazar

Gerard C. Blobe

William A. Boisvert

Nancy Bonini

Brendan Boyce

Jonathan Bromberg

Frank C. Brosius

Hal E. Broxmeyer

Michael J. Caplan

Diego H. Castrillon

Harold Chapman

Ajay Chawla

Benjamin K. Chen

Benny J. Chen

Ju Chen

Jun Chen

Marie-Françoise Chesselet

Vivian G. Cheung

Raymond Chung

Jeanne M. Clark

Sheila Collins

Ronald G. Collman

Marco Colonna

Shaun R. Coughlin

Tyler J. Curiel

David D'Alessio

Richard T. D'Aquila

Alan Daugherty

Sudhansu Dey

Anna Mae Diehl

Harry C. Dietz III

Gianpietro Dotti

Michael Dustin

Connie J. Eaves

Dominique Eladari

Joel K. Elmquist

Stephen G. Emerson

Jonathan A. Epstein

Adrian Erlebacher

Joel D. Ernst

James M. Ervasti

Robert V. Farese Jr.

Eric R. Fearon

Anthony W. Ferrante Jr.

Edward A. Fisher

Richard A. Flavell

Alessia Fornoni

Tatiana Foroud

Martin Friedlander

Stephen J. Galli

J. Victor Garcia-Martinez

Alfred L. George Jr.

Sharon Gerecht

Stanton L. Gerson

Robert E. Gerszten

Todd Golde

Sherita Golden

Stanley Goldfarb

Larry B. Goldstein

Fred Sanford Gorelick

Kathleen J. Green

Steven K. Grinspoon

David Hafler

Jonathan J. Hansen

Raymond Clement Harris

Stanley L. Hazen

Peter Heeringa

Meenhard Herlyn

Joachim Herz

Katherine A. High

Helen H. Hobbs

Ronald Hoffman

V. Michael Holers

Steven Holland

David Holtzman

Michael J. Holtzman

Lawrence B. Holzman

Tamas L. Horvath

Gokhan S. Hotamisligil

Steven R. Houser

Ralph H. Hruban

Christopher A. Hunter

David James

Richard J. Jones

William G. Kaelin Jr.

Klaus Kaestner

Mark L. Kahn

Raghu Kalluri

S. Ananth Karumanchi

David A. Kass

Robert S. Kass

Masato Kasuga

Daniel P. Kelly

Dontscho Kerjaschki

Sundeep Khosla

Richard N. Kitsis

Peter S. Klein

Steven Kliewer

Björn C. Knollmann

Walter J. Koch

Jay K. Kolls

Issei Komuro

Christopher D. Kontos

Murray Korc

Gary Koretzky

Stavroula Kousteni

John W. Krakauer

Rohit N. Kulkarni

Shelby Kutty

Chulan Kwon

Antonio La Cava

Fadi G. Lakkis

Terri Laufer

Mitchell A. Lazar

Brendan Lee

William M.F. Lee

Rudolph L. Leibel

Wayne I. Lencer

Jon D. Levine

Ross L. Levine

Klaus Ley

Rodger A. Liddle

Richard Locksley

Fanxin Long

Gary Lopaschuk

Nigel Mackman

Richard B. Mailman

Rama K. Mallampalli

Kieren A. Marr

Jack Martin

Steven O. Marx

Rodger P. McEver

Elizabeth McNally

Cornelis J. Melief

Shlomo Melmed

George Michalopoulos

Jeffrey H. Miner

Peter J. Mohler

Jeffery D. Molkentin

David D. Moore

Edward E. Morrisey

James H. Morrissey

Deborah M. Muoio

Anthony J. Muslin

Martin G. Myers Jr.

Benjamin G. Neel

Paul W. Noble

Eric N. Olson

Harry T. Orr

Leo E. Otterbein

Roberto Pacifici

Akhilesh Pandey

William C. Parks

Warren S. Pear

Sallie R. Permar

David J. Pinsky

Edward Plow

Catherine Postic

Alice S. Prince

Louis J. Ptáček

Luigi Puglielli

Pere Puigserver

Bali Pulendran

Ellen Puré

Susan E. Quaggin

Marlene Rabinovitch

Daniel J. Rader

Shahin Rafii

Gwendalyn J. Randolph

Jeffrey C. Rathmell

W. Kimryn Rathmell

Barbara Rehermann

Muredach P. Reilly

Jochen Reiser

Ryan Riddle

Sarah A. Robertson

Howard A. Rockman

Paul B. Rosenberg

Theodora S. Ross

Marc E. Rothenberg

Anil Rustgi

Scheherazade Sadegh-Nasseri

J. Evan Sadler

Junichi Sadoshima

Akira Sawa

Jose-Alain Sahel

Jean E. Schaffer

Philipp E. Scherer

Michael D. Schneider

Detlef Schuppan

Amita Sehgal

Clay Semenkovich

Jonathan S. Serody

John Seykora

Theresa A. Shapiro

Mari Shinohara

Steven E. Shoelson

Gerald I. Shulman

Roy L. Silverstein

M. Celeste Simon

Mihaela Skobe

Donald Small

Lois Smith

Akrit Sodhi

Weihong Song

Ashley L. St. John

Jonathan Stamler

Colin L. Stewart

Doris Stoffers

Warren Strober

Maureen A. Su

D. James Surmeier

Katalin Susztak

Catharina Svanborg

Ira Tabas

Alan R. Tall

Sakae Tanaka

Victor J. Thannickal

Andrei Thomas-Tikhonenko

Georgia D. Tomaras

Peter Tontonoz

Laurence A. Turka

Marcel R.M. van den Brink

Luc Van Kaer

David M. Virshup

Matthias von Herrath

Kathryn R. Wagner

Yisong Y. Wan

Bart O. Williams

Allan W. Wolkoff

Joseph C. Wu

Thomas A. Wynn

Ramnik J. Xavier

Mingzhao Xing

Yiping Yang

Srinivasan Yegnasubramanian

Mone Zaidi

Len Zon

Weiping Zou

R. Suzanne Zukin

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0 1

For the JCIEditorRexford S. Ahima

Deputy EditorsArturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli

Associate EditorsMark E. Anderson, Mary Y. Armanios, Nilofer S. Azad, Joel N. Blankson, William R. Bishai, Robert A. Brodsky, Peter A. Calabresi, Thomas L. Clemens, Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, Paul M. Hassoun, Maureen R. Horton, Elizabeth M. Jaffee, Mariana J. Kaplan, Marikki Laiho, Leo Luznik, Marcela V. Maus, Timothy H. Moran, Laszlo Nagy, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Jean-Pierre Raufman, Stuart C. Ray, Linda Smith Resar, Jeffrey D. Rothstein, Jonathan Schneck, Akrit S. Sodhi, Charlotte J. Sumner, Simeon I. Taylor, Robert G. Weiss, Sarah J. Wheelan, Marsha Wills-Karp

Editorial Advisory GroupPeter Agre, Carol W. Grieder, Diane E. Griffin, Paul B. Rothman, David Valle

BiostatisticianEliseo Guallar

Computational BiologistPatrick Cahan

JCI ScholarsDaniel Ardeljan, Robert M. Hughes, Mazen Tolaymat

Staff EditorsExecutive EditorSarah C. Jackson

Senior Science EditorCorinne Williams

Science EditorElyse Dankoski

Assistant Science EditorLisa Conti

Editor at LargeUshma S. Neill

Editorial InternBouchra Taib

JCI This Month ISSN 2380-3029 (print)ISSN 2380-3037 (online)For the full JCI online: jci.me/130/3

This MonthMarch 2020

Contact the JCI and JCI Insight2015 Manchester Road, Ann Arbor, Michigan 48104, USAPhone: 734.222.6050Email: staff@the-jci.org (JCI); staff@insight.jci.org (JCI Insight)

The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation and JCI Insight. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

(ASCI) indicates corresponding authors who are ASCI members.

Marikki Laiho, MD, PhD, Associate Editor, is the Willard and Lillian Hackerman Professor of Radiation Oncology, Professor in Radiation Oncology and Oncology at Johns Hopkins University School of Medicine, and Director of the Molecular Radiation Sciences research division in the Department of Radiation Oncology. Dr. Laiho’s research focuses on DNA damage biology and in developing new therapeutic agents targeting cellular transcriptional programs altered in cancer. In addition to her work with the JCI, she serves on the editorial board of The Prostate.

Publication highlights

Low JY, Sirajuddin P, Moubarek M, Agarwal S, Rege A, Guner G, Liu H, Yang Z, De Marzo AM, Bieberich C, Laiho M. Effective targeting of RNA polymerase I in treatment-resistant prostate cancer. Prostate. 2019;79(16):1837–1851.

Wei T, Najmi SM, Liu H, Peltonen K, Kucerova A, Schneider DA, Laiho M. Small-molecule targeting of RNA polymerase I activates a conserved transcription elongation checkpoint. Cell Rep. 2018;23(2):404–414.

Guner G, Sirajuddin P, Zheng Q, Bai B, Brodie A, Liu H, Af Hällström T, Kulac I, Laiho M, De Marzo AM. Novel assay to detect RNA polymerase I activity in vivo. Mol Cancer Res. 2017;15(5):577–584.

Peltonen K, Colis L, Liu H, Jäämaa S, Zhang Z, Af Hällström T, Moore HM, Sirajuddin P, Laiho M. Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress. Mol Cancer Ther. 2014;13(11):2537–2546.

Peltonen K, Colis L, Liu H, Trivedi R, Moubarek MS, Moore HM, Bai B, Rudek MA, Bieberich CJ, Laiho M. A targeting modality for destruction of RNA polymerase I that possesses anticancer activity. Cancer Cell. 2014;25(1):77–90.

The JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.

Featured Editor

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 02

research

Editor’s pickson the jci cover oncology

Targeting proangiogenic pathway boosts immunotherapy response in Apc-mutant intestinal tumorsOutcomes vary widely for patients with colorectal cancer (CRC), and tumors supported by denser stromal and vascular tissue are associated with the worst prognoses. In genetic models of cancer, there is evidence that antifibrotic or antiangio-genic cotreatment may improve response to immunotherapy; however, to date, attempts to target the tumor microenvironment and elicit a productive antitumor immune response in CRC have been unsuccessful. In this issue, Simone Ragusa et al. reveal that the transcription factor PROX1 may possess antifibrotic and antiangiogenic functions in aggressive subtypes of CRC. PROX1 is a well-known marker for lymphatic endothelial cells, but in CRC it becomes highly expressed in tumor cells in response to elevated WNT signaling. In patients with CRC, lower PROX1 expression correlated with worse clinical outcomes and increased stromal gene signatures. Using conditional Apc-mutant mice to model CRC, the authors revealed that loss of Prox1 led to overexpression of the profibrotic metalloproteinase MMP14, resulting in increased angiogenesis, stromal activation, and intestinal tumor growth. Moreover, although Prox1-expressing tumors responded well to 5-FU–based chemotherapy, Prox1-deficient tumors were highly resistant, coincident with stromal activation that promoted tumor progression. Combining antiangiogenic therapies with a CD40-activating antibody normalized angiogenesis in Apc-mutant tumors but also downregulated Mmp14 expression, which reduced fibrosis and unleashed cancer cell killing by cytotoxic lymphocytes. In the accompanying Commentary, Lena Claesson-Welsh indicates that tumor vasculature could potentially be targeted to make some therapy-resistant CRCs responsive to immune interventions. The cover image conveys the fibrotic nature of the Apc-mutant intestinal tumors, showing tumor epithelial cells (E-cadherin, white; Ki-67, green) surrounded by stroma (α-SMA, red). Image credit: Simone Ragusa.

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in miceSimone Ragusa, Borja Prat-Luri, Alejandra González-Loyola, Sina Nassiri, Mario Leonardo Squadrito, Alan Guichard, Sabrina Cavin, Nikolce Gjorevski, David Barras, Giancarlo Marra, Matthias P. Lutolf, Jean Perentes, Emily Corse, Roberta Bianchi, Laureline Wetterwald, Jaeryung Kim, Guillermo Oliver, Mauro Delorenzi, Michele De Palma, and Tatiana V. Petrova http://jci.me/129558

Related CommentaryHow the matrix metalloproteinase MMP14 contributes to the progression of colorectal cancerLena Claesson-Welsh http://jci.me/135239

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0 3

clinical medicine

JCI | Research: Editor’s picks

Serum sphingolipids as candidate biomarkers for coronary artery disease

CD8+ T cells target the brain vasculature in pediatric cerebral malaria

Coronary artery disease (CAD) is associated with aberrant serum lipid profiles, including abnormal levels of triglycerides, cholesterol, and sphingolipids. Sphingolipids and their metabolites, ceramides, play important roles in cellular architecture, signaling, and metabolism and may represent valuable biomarkers in cardiovascular conditions. Annelise Poss and colleagues identified links between sphingolipid levels and CAD risk in 462 patients with CAD and 212 healthy controls. They used unbiased machine learning to develop a risk score based on sphingolipid-inclusive lipidomic analyses and showed that it predicts CAD risk more effectively than traditional LDL-cholesterol and serum triglyceride measurements alone. In the accompanying Commentary, Justin Echouffo-Tcheugui, Mohit Jain, and Susan Cheng support the potential use of serum sphingolipid and ceramide measurements as cholesterol-independent biomarkers for CAD and cardiovascular disease risk.

Malaria is disproportionately fatal in young children, and the majority of malaria- associated fatalities are linked to cerebral malaria, a complication that does not adequately respond to intravenous antimalarial therapy. Models of cerebral malaria have implicated CD8+ T cells in pathogenesis, but lack of human corroboration has slowed efforts to identify therapeutic targets. Brittany Riggle, Monica Manglani, and collaborators performed multiplex immunohistochemistry in postmortem brain samples from children with or without cerebral malaria and with known HIV status. Cerebral malaria diagnosis was associated with elevated numbers of CD3+CD8+ T cells engaging with the cerebrovasculature. In the setting of HIV coinfection, the researchers observed further increases in CD3+CD8+ T cell engagement as well as enhanced distribution into the cerebral perivasculature. In the accompanying commentary, Laurent Rénia, Georges Grau, and Samuel Wassmer detail the rationale for investigating CD3+CD8+ T cells as the target of an adjunctive therapy for cerebral malaria.

CD8+ T cells target cerebrovasculature in children with cerebral malariaBrittany A. Riggle, Monica Manglani, Dragan Maric, Kory R. Johnson, Myoung-Hwa Lee, Osorio Lopes Abath Neto, Terrie E. Taylor, Karl B. Seydel, Avindra Nath, Louis H. Miller, Dorian B. McGavern, and Susan K. Pierce http://jci.me/133474

Related CommentaryCD8+ T cells and human cerebral malaria: a shifting epistemeLaurent Rénia, Georges E.R. Grau, and Samuel C. Wassmer http://jci.me/135510

Machine learning reveals serum sphingolipids as cholesterol-independent biomarkers of coronary artery diseaseAnnelise M. Poss, J. Alan Maschek, James E. Cox, Benedikt J. Hauner, Paul N. Hopkins, Steven C. Hunt, William L. Holland, Scott A. Summers, and Mary C. Playdon http://jci.me/131838

Related CommentaryBreaking through the surface: more to learn about lipids and cardiovascular diseaseJustin B. Echouffo-Tcheugui, Mohit Jain, and Susan Cheng http://jci.me/134696

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 04

JCI | Research: Editor’s picks

neuroscience

cardiology

Potassium channel inhibition reverses cardiovascular abnormalities in Cantu syndrome mice

Prion protein glycosylation influences pathological plaque formation in miceRapid formation of protein aggregates is associated with expedited clinical progression in certain neurodegenerative conditions, including prion diseases. Posttranslational modifications affecting protein structure likely influence pathological aggregation and therefore disease progression. Alejandro Sevillano, Patricia Aguilar-Calvo, and colleagues focused on the contribution of glycans on the cellular prion protein, PrPC, in guiding protein assembly and aggregation. They

developed an in vivo mouse model expressing an underglycosylated form of PrPC (Prnp18OQ/196Q mice) and observed that Prnp18OQ/196Q mice exhibited increased plaque deposits following infection with diverse prion strains, despite normal PrPC expression and trafficking (see the associated image). Enhanced plaque formation in the Prnp18OQ/196Q mice was also associated with more severe neuronal degeneration. The increased affinity of underglycosylated PrPC for heparan

sulfate implied that WT PrPC glycans interfere with heparan sulfate binding and related plaque formation. Jason Bartz’s accompanying Commen-tary discusses these insights, which support further investigation of protein modification strategies as opportunities to modify prion disease progression.

Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion diseaseAlejandro M. Sevillano, Patricia Aguilar-Calvo, Timothy D. Kurt, Jessica A. Lawrence, Katrin Soldau, Thu H. Nam, Taylor Schumann, Donald P. Pizzo, Sofie Nyström, Biswa Choudhury, Hermann Altmeppen, Jeffrey D. Esko, Markus Glatzel, K. Peter R. Nilsson, and Christina J. Sigurdson http://jci.me/131564

Related CommentaryUnderglycosylated prion protein modulates plaque formation in the brainJason C. Bartz http://jci.me/134842

In Cantu syndrome (CS), cardiac abnormalities including dilated vasculature and cardiac hypertrophy are driven by gain-of-function mutations in specific subunits of ATP-sensitive potassium channels (KATP channels) expressed in vascular smooth muscle (VSM). Conor McClen-aghan and colleagues used a mouse model of CS to investigate whether targeting these KATP channels can reverse cardiovascular remodeling in this disease. In adult CS mice, genetic inhibition of VSM KATP channels mitigated both cardiac and vascular phenotypes, suggesting that aspects of the syndrome are reversible after they manifest. Next, CS mice were treated with glibenclamide, a clinically approved KATP channel inhibitor, for four weeks. Dose-dependent reductions in cardiac hypertrophy and other abnormalities were noted. In the accompanying Commentary, Guiling Zhao, Aaron Kaplan, Maura Greiser, and Jonathan Lederer indicate that

blocking pathological KATP channel function could be beneficial as a targeted therapy for CS.

Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivityConor McClenaghan, Yan Huang, Zihan Yan, Theresa Harter, Carmen M. Halabi, Rod Chalk, Attila Kovacs, Gijs van Haaften, Maria S. Remedi, and Colin G. Nichols http://jci.me/130571

Related CommentaryThe surprising complexity of KATP channel biology and genetic diseasesGuiling Zhao, Aaron Kaplan, Maura Greiser, and W. Jonathan Lederer http://jci.me/135759

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0 5

JCI | Research: Editor’s picks

immunology

T cell metabolism is altered in patients with chronic fatigue syndromeChronic fatigue syndrome (CFS) is characterized by flu-like inflammatory symptoms accompanied by severe fatigue and malaise. Metabolic and immune alterations in patients with CFS suggest that immunometabolic dysfunction contributes to pathogenesis, but more information is needed to identify potential therapeutic targets. Alexandra Mandarano and colleagues profiled CD8+ and CD4+ T cell metabolism in 53 patients with CFS and 45 healthy volunteers. Both CD8+ and CD4+ T cells isolated from CFS samples displayed alterations in glucose metabolism relative to healthy controls, and CD8+ T cells showed reduced mitochondrial membrane potential. These alterations in T cell metabolism were uniquely correlated with plasma cytokine abundance in patients with CFS. Mady Hornig’s accompanying Commen-tary discusses how these associations, in addition to specific T cell metabolic disturbances in patients with CFS, provide much-needed insights into mechanisms underlying immune dysfunction in this disease.

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associationsAlexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson http://jci.me/132185

Related CommentaryCan the light of immunometabolism cut through “brain fog”?Mady Hornig http://jci.me/134985

IL-36γ induction underlies skin toxicity associated with EGFR inhibitorsTreatment-related skin toxicity is a major limitation of EGFR/MEK-blocking cancer therapies. Over half of treated patients will develop acneiform eruptions that are characterized by neutrophil infiltration and inflammation mainly at sebum-rich skin sites. Takashi Satoh and colleagues analyzed gene expression in skin biopsies from affected patients and identified the proinflammatory cytokine IL-36γ as a driver of EGFR inhibitor–driven skin toxicity. In human keratinocytes, they verified that exposure to the EGFR inhibitor erlotinib increased IL-36γ induction. Moreover, erlotinib synergized with the skin commensal bacterium Cutibacterium acnes to further enhance IL-36γ induction, providing an explanation for the distribution of eruptions on the face, upper chest, and back. Erlotinib-associated increases in IL-36γ were associated with increased expression of the transcription factor KLF4, which binds to the IL-36γ gene promoter (see the associated image). In the accompanying Commentary, Allison Billi, Mrinal Sarkar, and Johan Godjohnsson highlight KLF4 and IL-36γ as potential targets for mitigating EGFR/MEK inhibitor–associated skin toxicity.

IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnesTakashi K. Satoh, Mark Mellett, Barbara Meier-Schiesser, Gabriele Fenini, Atsushi Otsuka, Hans-Dietmar Beer, Tamara Rordorf, Julia-Tatjana Maul, Jürg Hafner, Alexander A. Navarini, Emmanuel Contassot, and Lars E. French http://jci.me/128678

Related CommentaryWhen bugs and drugs conspire: driving acneiform skin toxicityAllison C. Billi, Mrinal K. Sarkar, and Johann E. Gudjonsson (ASCI) http://jci.me/133787

Chikungunya virus replication in skeletal muscle mediates pathological inflammationChikungunya virus (CHIKV) infection produces fever, rash, arthritis, and myalgia that can persist for months or years. Due to the virus’s broad tissue tropism, the mechanisms underlying the disease’s clinical course remain unclear. Anthony Lentscher and colleagues engineered a muscle-specific, replication-restricted variant of CHIKV to assess whether CHIKV replication in skeletal muscle cells is required for disease pathogenesis. Mice infected with restricted CHIKV displayed less muscle inflammation and necrosis compared with mice infected with unrestricted muscle-specific variants and wild-type CHIKV. Moreover, T cell infiltration and inflammatory cytokine production were diminished in restricted CHIKV-infected muscle. The researchers identified increased IL-6 production as a critical mediator of inflammation in CHIKV-infected muscle, suggesting that IL-6–blocking antibodies could be used to treat CHIKV disease. Anne Moscona discusses the implications for development of a CHIKV vaccine in the accompanying Commentary.

Chikungunya virus replication in skeletal muscle cells is required for disease developmentAnthony J. Lentscher, Mary K. McCarthy, Nicholas A. May, Bennett J. Davenport, Stephanie A. Montgomery, Krishnan Raghunathan, Nicole McAllister, Laurie A. Silva, Thomas E. Morrison, and Terence S. Dermody (ASCI) http://jci.me/129893

Related CommentaryChikungunya infection: de-linking replication from symptomatology reveals the central role of muscleAnne Moscona (ASCI) http://jci.me/134746

infectious disease

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 06

JCI | Features

conversations with giants in medicine

review

viewpoint

Senescent T cells in cancer and immunotherapy

Barbara KahnEndocrinologist Barbara Kahn is Professor of Medicine at Harvard Medical School and Vice Chair for Research Strategy at Beth Israel Deaconess Medical Center. Dr. Kahn’s discoveries include groundbreaking work on the mechanisms of glucose metabolism in adipocytes, and her recent work focuses on a new class of bioactive lipids that show beneficial effects against inflammation and insulin resistance. Recently, she sat down with JCI Editor at Large Ushma Neill to discuss her decision to pursue medicine and the steps that led her to study glucose transport. The full interview is available on the JCI website.

http://jci.me/136339

Clinical insights into managing heart diseaseIn this issue, a Viewpoint by Thorsten Leucker, Steven Schulman, and Gary Gerstenblith summarizes the outcomes of the ISCHEMIA trial, which enrolled more than 5000 patients with ischemic heart disease to evaluate the outcomes associated with invasive versus conservative management. All patients in the study received prescribed medical therapy that included lifestyle changes and medications such as cholesterol-lowering drugs. Patients randomized to invasive management were assessed for coronary artery disease, and if disease was present, they received coronary revascularization. In contrast, patients in the conservative management group received coronary revasularization only if medical therapy did not improve angina and other symptoms of ischemic heart disease. The trial’s findings imply that invasive management may more effectively reduce ischemic heart disease symptoms, but it does not significantly reduce the rate of myocardial infarction or cardiovasculature-related fatalities.

Stable ischemic heart disease: how to keep it that wayThorsten M. Leucker, Steven P. Schulman, and Gary Gerstenblith http://jci.me/135959

Immune dysfunction in the tumor microenvironment profoundly influences antitumor immunity and the efficacy of immunotherapeutic treatments. While much research has focused on the effects of T cell exhaustion in tumor immune evasion and anticancer strategies, senescent T cells also contribute to a suppressive tumor microenvironment. In this Review, Xia Liu, Daniel Hoft, and Guangyong Peng discuss mechanisms that may induce T cell senescence in the setting of cancer, the distinct characteristics of senescent T cells, and the effect of T cell senescence in tumorigenesis and resistance to immunotherapy (see the accompanying image). Their insights emphasize that further work to delineate dysfunctional immune states in cancer will be essential for improving the efficacy of these treatments.

Senescent T cells within suppressive tumor microenvironments: emerging target for tumor immunotherapyXia Liu, Daniel F. Hoft, and Guangyong Peng http://jci.me/133679

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0 7

Current research articles

cardiologyGlibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity p. 4Conor McClenaghan, Yan Huang, Zihan Yan, Theresa Harter, Carmen M. Halabi, Rod Chalk, Attila Kovacs, Gijs van Haaften, Maria S. Remedi, and Colin G. Nichols http://jci.me/130571

Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-αM. Ahsan Siraj, Dhanwantee Mundil, Sanja Beca, Abdul Momen, Eric A. Shikatani, Talat Afroze, Xuetao Sun, Ying Liu, Siavash Ghaffari, Warren Lee, Michael B. Wheeler, Gordon Keller, Peter Backx, and Mansoor Husain http://jci.me/99934

clinical medicineDGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosisBarbara Rivera, Javad Nadaf, Somayyeh Fahiminiya, Maria Apellaniz-Ruiz, Avi Saskin, Anne-Sophie Chong, Sahil Sharma, Rabea Wagener, Timothée Revil, Vincenzo Condello, Zineb Harra, Nancy Hamel, Nelly Sabbaghian, Karl Muchantef, Christian Thomas, Leanne de Kock, Marie-Noëlle Hébert-Blouin, Angelia V. Bassenden, Hannah Rabenstein, Ozgur Mete, Ralf Paschke, Marc P. Pusztaszeri, Werner Paulus, Albert Berghuis, Jiannis Ragoussis, Yuri E. Nikiforov, Reiner Siebert, Steffen Albrecht, Robert Turcotte, Martin Hasselblatt, Marc R. Fabian, and William D. Foulkes http://jci.me/130206

Machine learning reveals serum sphingolipids as cholesterol-independent biomarkers of coronary artery disease p. 3Annelise M. Poss, J. Alan Maschek, James E. Cox, Benedikt J. Hauner, Paul N. Hopkins, Steven C. Hunt, William L. Holland, Scott A. Summers, and Mary C. Playdon http://jci.me/131838

Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase 1 trialPeter A. Campochiaro, Mustafa Iftikhar, Gulnar Hafiz, Anam Akhlaq, Grace Tsai, Dagmar Wehling, Lili Lu, G. Michael Wall, Mandeep S. Singh, and Xiangrong Kong http://jci.me/132990

CD8+ T cells target cerebrovasculature in children with cerebral malaria p. 3Brittany A. Riggle, Monica Manglani, Dragan Maric, Kory R. Johnson, Myoung-Hwa Lee, Osorio Lopes Abath Neto, Terrie E. Taylor, Karl B. Seydel, Avindra Nath, Louis H. Miller, Dorian B. McGavern, and Susan K. Pierce http://jci.me/133474

hematologyA stress-responsive enhancer induces dynamic drug resistance in acute myeloid leukemiaMark S. Williams, Fabio M.R. Amaral, Fabrizio Simeoni, and Tim C.P. Somervaille http://jci.me/130809

Microphthalmia transcription factor expression contributes to bone marrow failure in Fanconi anemiaAlessia Oppezzo, Julie Bourseguin, Emilie Renaud, Patrycja Pawlikowska, and Filippo Rosselli http://jci.me/131540

immunologyOral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndromeAngela C. Sosa, Barbara Kariuki, Qi Gan, Alan P. Knutsen, Clifford J. Bellone, Miguel A. Guzmán, Luis A. Barrera, Shunji Tomatsu, Anil K. Chauhan, Eric Armbrecht, and Adriana M. Montaño http://jci.me/125607

IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes p. 5Takashi K. Satoh, Mark Mellett, Barbara Meier-Schiesser, Gabriele Fenini, Atsushi Otsuka, Hans-Dietmar Beer, Tamara Rordorf, Julia-Tatjana Maul, Jürg Hafner, Alexander A. Navarini, Emmanuel Contassot, and Lars E. French http://jci.me/128678

The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptorsBianca Balbino, Pauline Herviou, Ophélie Godon, Julien Stackowicz, Odile Richard-Le Goff, Bruno Iannascoli, Delphine Sterlin, Sébastien Brûlé, Gael A. Millot, Faith M. Harris, Vera A. Voronina, Kari C. Nadeau, Lynn E. Macdonald, Andrew J. Murphy, Pierre Bruhns, and Laurent L. Reber http://jci.me/129697

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 08

Current research articles

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations p. 5Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson http://jci.me/132185

infectious diseaseChikungunya virus replication in skeletal muscle cells is required for disease development p. 5Anthony J. Lentscher, Mary K. McCarthy, Nicholas A. May, Bennett J. Davenport, Stephanie A. Montgomery, Krishnan Raghunathan, Nicole McAllister, Laurie A. Silva, Thomas E. Morrison, and Terence S. Dermody (ASCI) http://jci.me/129893

Staphylococcus aureus toxin suppresses antigen-specific T cell responsesBrandon Lee, Reuben Olaniyi, Jakub M. Kwiecinski, and Juliane Bubeck Wardenburg (ASCI) http://jci.me/130728

metabolismInsulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver diseaseGordon I. Smith, Mahalakshmi Shankaran, Mihoko Yoshino, George G. Schweitzer, Maria Chondronikola, Joseph W. Beals, Adewole L. Okunade, Bruce W. Patterson, Edna Nyangau, Tyler Field, Claude B. Sirlin, Saswata Talukdar, Marc K. Hellerstein, and Samuel Klein (ASCI) http://jci.me/134165

muscle biologyAnnexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activationSimon McArthur, Gaëtan Juban, Thomas Gobbetti, Thibaut Desgeorges, Marine Theret, Julien Gondin, Juliana E. Toller-Kawahisa, Chris P. Reutelingsperger, Bénédicte Chazaud, Mauro Perretti, and Rémi Mounier http://jci.me/124635

Muscle-specific SMN reduction reveals motor neuron–independent disease in spinal muscular atrophy modelsJeong-Ki Kim, Narendra N. Jha, Zhihua Feng, Michelle R. Faleiro, Claudia A. Chiriboga, Lan Wei-Lapierre, Robert T. Dirksen, Chien-Ping Ko, and Umrao R. Monani http://jci.me/131989

nephrologyGlycerol-3-phosphate is an FGF23 regulator derived from the injured kidneyPetra Simic, Wondong Kim, Wen Zhou, Kerry A. Pierce, Wenhan Chang, David B. Sykes, Najihah B. Aziz, Sammy Elmariah, Debby Ngo, Paola Divieti Pajevic, Nicolas Govea, Bryan R. Kestenbaum, Ian H. de Boer, Zhiqiang Cheng, Marta Christov, Jerold Chun, David E. Leaf, Sushrut S. Waikar, Andrew M. Tager, Robert E. Gerszten, Ravi I. Thadhani, Clary B. Clish, Harald Jüppner, Marc N. Wein, and Eugene P. Rhee http://jci.me/131190

neuroscienceD1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s diseaseIrene Sebastianutto, Elise Goyet, Laura Andreoli, Joan Font-Ingles, David Moreno-Delgado, Nathalie Bouquier, Céline Jahannault-Talignani, Enora Moutin, Luisa Di Menna, Natallia Maslava, Jean-Philippe Pin, Laurent Fagni, Ferdinando Nicoletti, Fabrice Ango, M. Angela Cenci, and Julie Perroy http://jci.me/126361

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathyJeremy M. Sullivan, William W. Motley, Janel O. Johnson, William H. Aisenberg, Katherine L. Marshall, Katy E.S. Barwick, Lingling Kong, Jennifer S. Huh, Pamela C. Saavedra-Rivera, Meriel M. McEntagart, Marie-Helene Marion, Lucy A. Hicklin, Hamid Modarres, Emma L. Baple, Mohamed H. Farah, Aamir R. Zuberi, Cathleen M. Lutz, Rachelle Gaudet, Bryan J. Traynor, Andrew H. Crosby, and Charlotte J. Sumner (ASCI) http://jci.me/128152

Neuromuscular junctions are stable in patients with cancer cachexiaInes Boehm, Janice Miller, Thomas M. Wishart, Stephen J. Wigmore, Richard J.E. Skipworth, Ross A. Jones, and Thomas H. Gillingwater http://jci.me/128411

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actionsDanielle M. Gerhard, Santosh Pothula, Rong-Jian Liu, Min Wu, Xiao-Yuan Li, Matthew J. Girgenti, Seth R. Taylor, Catharine H. Duman, Eric Delpire, Marina Picciotto, Eric S. Wohleb, and Ronald S. Duman http://jci.me/130808

Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALSKaitlin Weskamp, Elizabeth M. Tank, Roberto Miguez, Jonathon P. McBride, Nicolás B. Gómez, Matthew White, Ziqiang Lin, Carmen Moreno Gonzalez, Andrea Serio, Jemeen Sreedharan, and Sami J. Barmada http://jci.me/130988

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0 9

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disabilityLin Li, Mohammad Ghorbani, Monika Weisz-Hubshman, Justine Rousseau, Isabelle Thiffault, Rhonda E. Schnur, Catherine Breen, Renske Oegema, Marjan M.M. Weiss, Quinten Waisfisz, Sara Welner, Helen Kingston, Jordan A. Hills, Elles M.J. Boon, Lina Basel-Salmon, Osnat Konen, Hadassa Goldberg-Stern, Lily Bazak, Shay Tzur, Jianliang Jin, Xiuli Bi, Michael Bruccoleri, Kirsty McWalter, Megan T. Cho, Maria Scarano, G. Bradley Schaefer, Susan S. Brooks, Susan Starling Hughes, K.L.I. van Gassen, Johanna M. van Hagen, Tej K. Pandita, Pankaj B. Agrawal, Philippe M. Campeau, and Xiang-Jiao Yang http://jci.me/131145

Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease p. 4Alejandro M. Sevillano, Patricia Aguilar-Calvo, Timothy D. Kurt, Jessica A. Lawrence, Katrin Soldau, Thu H. Nam, Taylor Schumann, Donald P. Pizzo, Sofie Nyström, Biswa Choudhury, Hermann Altmeppen, Jeffrey D. Esko, Markus Glatzel, K. Peter R. Nilsson, and Christina J. Sigurdson http://jci.me/131564

Impaired folate one-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase–deficient miceChloe Santos, Yun Jin Pai, M. Raasib Mahmood, Kit-Yi Leung, Dawn Savery, Simon N. Waddington, Andrew J. Copp, and Nicholas D.E. Greene http://jci.me/132360

oncologyA conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer targetZachary T. Freeman, Thomas R. Nirschl, Daniel H. Hovelson, Robert J. Johnston, John J. Engelhardt, Mark J. Selby, Christina M. Kochel, Ruth Y. Lan, Jingyi Zhai, Ali Ghasemzadeh, Anuj Gupta, Alyza M. Skaist, Sarah J. Wheelan, Hui Jiang, Alexander T. Pearson, Linda A. Snyder, Alan J. Korman, Scott A. Tomlins, Srinivasan Yegnasubramanian, and Charles G. Drake http://jci.me/128672

CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironmentShi Yong Neo, Ying Yang, Julien Record, Ran Ma, Xinsong Chen, Ziqing Chen, Nicholas P. Tobin, Emily Blake, Christina Seitz, Ron Thomas, Arnika Kathleen Wagner, John Andersson, Jana de Boniface, Jonas Bergh, Shannon Murray, Evren Alici, Richard Childs, Martin Johansson, Lisa S. Westerberg, Felix Haglund, Johan Hartman, and Andreas Lundqvist http://jci.me/128895

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice p. 2Simone Ragusa, Borja Prat-Luri, Alejandra González-Loyola, Sina Nassiri, Mario Leonardo Squadrito, Alan Guichard, Sabrina Cavin, Nikolce Gjorevski, David Barras, Giancarlo Marra, Matthias P. Lutolf, Jean Perentes, Emily Corse, Roberta Bianchi, Laureline Wetterwald, Jaeryung Kim, Guillermo Oliver, Mauro Delorenzi, Michele De Palma, and Tatiana V. Petrova http://jci.me/129558

Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapiesRong Fu, Yi Li, Nan Jiang, Bo-Xue Ren, Chen-Zi Zang, Li-Juan Liu, Wen-Cong Lv, Hong-Mei Li, Stephen Weiss, Zheng-Yu Li, Tao Lu, and Zhao-Qiu Wu http://jci.me/131507

pulmonologyLinear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infectionPatricia L. Brazee, Luisa Morales-Nebreda, Natalia D. Magnani, Joe G.N. Garcia, Alexander V. Misharin, Karen M. Ridge, G.R. Scott Budinger, Kazuhiro Iwai, Laura A. Dada, and Jacob I. Sznajder http://jci.me/128368

transplantationGraft-versus-host disease of the CNS is mediated by TNF upregulation in microgliaNimitha R. Mathew, Janaki M. Vinnakota, Petya Apostolova, Daniel Erny, Shaimaa Hamarsheh, Geoffroy Andrieux, Jung-Seok Kim, Kathrin Hanke, Tobias Goldmann, Louise Chappell-Maor, Nadia El-Khawanky, Gabriele Ihorst, Dominik Schmidt, Justus Duyster, Jürgen Finke, Thomas Blank, Melanie Boerries, Bruce R. Blazar, Steffen Jung, Marco Prinz, and Robert Zeiser http://jci.me/130272

vascular biologyChronic mTOR activation induces a degradative smooth muscle cell phenotypeGuangxin Li, Mo Wang, Alexander W. Caulk, Nicholas A. Cilfone, Sharvari Gujja, Lingfeng Qin, Pei-Yu Chen, Zehua Chen, Sameh Yousef, Yang Jiao, Changshun He, Bo Jiang, Arina Korneva, Matthew R. Bersi, Guilin Wang, Xinran Liu, Sameet Mehta, Arnar Geirsson, Jeffrey R. Gulcher, Thomas W. Chittenden, Michael Simons, Jay D. Humphrey, and George Tellides http://jci.me/131048

Flip issue to read JCI Insight content.

jci.org/this-month

HSPC alterations underlie bone marrow failure 13

Neutrophil dysfunction in idiopathic inflammatory myopathies 12

Long-term immunity linked with measles virus RNA persistence 11

JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight

March 2020

Immune cell landscape of kidney fibrosis and regeneration p. 11

This Month

17

Pilar Alcaide

John F. Alcorn

Maria-Luisa Alegre

Ravi K. Amaravadi

Cristian Apetrei

Rajendra S. Apte

Zoltan Arany

Hossein Ardehali

Julio Ayala

Sami J. Barmada

Alexander G. Bassuk

Vann Bennett

Sudha B. Biddinger

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

Sebastien G. Bouret

Jason Brenchley

Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

Stephen Y. Chan

Timothy A. Chan

Yuan Chang

Benjamin K. Chen

Kang Chen

Zhou-Feng Chen

Wendy Chung

Matthew Ciorba

Janice E. Clements

Craig M. Coopersmith

George Cotsarelis

Peter A. Crawford

Lisa L. Cunningham

Jennifer Davis

Ronald P. DeMatteo

Madhav V. Dhodapkar

Elia J. Duh

Sarah K. England

Carmella Evans-Molina

Robert L. Fairchild

Eric R. Fearon

Brian Finck

John H. Fingert

Robert Flaumenhaft

Edward A. Fon

Lawrence Fong

Nikolaos G. Frangogiannis

Anthony R. French

Katherine A. Gallagher

Terrence L. Geiger

Raphaela Goldbach-Mansky

Daniel R. Goldstein

Douglas K. Graham

Johann E. Gudjonsson

Kirk Habegger

Khalid A. Hanafy

Eric B. Haura

John Cijiang He

Adam Steven Helms

Robert O. Heuckeroth

Cory M. Hogaboam

Young-Kwon Hong

Eric J. Huang

Benjamin D. Humphreys

Ken Inoki

Rajan Jain

Daniel P. Judge

J. Michelle Kahlenberg

Shingo Kajimura

Pawel Kalinski

Nobuhiko Kamada

Thomas W.H. Kay

Barbara I. Kazmierczak

Catherine E. Keegan

Hans-Peter Kiem

William Y. Kim

Frank Kirchhoff

David G. Kirsch

Jason S. Knight

Donald E. Kohan

Maria Kontaridis

Laura A. Kresty

Jongsoon Lee

Michael Lehrke

Claire E. Lewis

Mathias Lichterfeld

Rodger A. Liddle

André Lieber

Michail S. Lionakis

Ivan Maillard

Ziad Mallat

Peter Mannon

Eric Martens

Franck Mauvais-Jarvis

Linda McAllister-Lucas

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

David K. Meyerholz

Jason C. Mills

Joshua D. Milner

Satdarshan Paul Monga

Hidayatullah G. Munshi

William J. Murphy

Matthias Nahrendorf

Mary C. Nakamura

Patrick Nana-Sinkam

Lisa F.P. Ng

Mark Nicolls

Laura J. Niedernhofer

Una O’Doherty

S. Tiong Ong

Akira Ono

Puneet Opal

Olabisi Opeyemi

Daniel Ory

Sophie Paczesny

Rulan Parekh

Victoria N. Parikh

Mary-Elizabeth Patti

Janos Peti-Peterdi

Fernando P. Polack

Benjamin Prosser

Ling Qi

Dominic Raj

Jalees Rehman

Florian Rieder

Matthew D. Ringel

Howard A. Rockman

Steven M. Rowe

Linda C. Samuelson

Victoria L. Seewaldt

Svati H. Shah

Vijay H. Shah

Yatrik M. Shah

Vikram Shakkottai

Guo-Ping Shi

Kanakadurga Singer

Natasha Snider

Scott Soleimanpour

Rhonda F. Souza

Fayyaz S. Sutterwala

Shu Takeda

James E. Talmadge

Muneesh Tewari

John P. Thyfault

Natalie J. Torok

Stephen H. Tsang

Hubert M. Tse

Fumihiko Urano

Jolanda van der Velden

Deborah J. Veis

Charles P. Venditti

Claudio J. Villanueva

Joseph Vinetz

Stephanie M. Ware

Sing Sing Way

Kevin W. Williams

Minna Woo

Prescott G. Woodruff

Jing Yang

Tianxin Yang

Yiping Yang

Vincent B. Young

Lori M. Zeltser

Zhen Zhang

Yutong Zhao

Binhua P. Zhou

JCI Insight Consulting Editors

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0 10

For JCI InsightEditorKathleen CollinsDeputy EditorsAndrew Lieberman, Donna Martin, Pavan ReddyAssociate EditorsSharlene M. Day, Gregory R. Dressler, David A. Fox, Santhi Ganesh, John Y. Kao, Nobuhiko Kamada, Celina G. Kleer, Carey Lumeng, Lona Mody, Bethany B. Moore, Marina Pasca di Magliano, Subramaniam Pennathur, Darleen Sandoval, Andrew Tai, Weiping ZouExecutive EditorSarah C. JacksonSenior Science EditorCorinne WilliamsComputational BiologistAlexey NesvizhskiiJCI Insight ScholarsHannah Bell, Fred Shen, Andrea D. Thompson

ASCI StaffExecutive Director John B. HawleyManaging Director Karen D. GuthAssociate Director Maya HoptmanAssociate Director, Technology Shawn PyleProduction EditorsCatherine Ahmann, Ken Beauchamp, Molly Jean, Lara L. McCarronProduction Assistant Samantha SmithScientific Illustrator Bruce WordenCopy EditorsClare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, Chet ProvodaAssociate Copy EditorsDarla Nagel, Megan ReilleyAssociate Editor, Copy and ProductionRachel BullenEditorial Assistant Cady VishniacAccounts Manager Paula KremidasAuthor Services ManagerMegan JenkinsAuthor Sevices RepresentativesKatherine A. Bullen, Keith KalinowskiExecutive Administrator Theresa KaiserScience Communications SpecialistNeha AggarwalProgram Manager Ashley HastonSystem Administrator and DeveloperBryan EnglishSoftware DevelopersAustin Brewer, Jose L. Jardon

This MonthMarch 2020

For JCI Insight online: jci.me/insight/5/3jci.me/insight/5/4

David Fox, MD, Associate Editor, is Professor of Internal Medicine, Co-Director of the Clinical Autoimmunity Center of Excellence, and the Frederick G.L. Huetwell and William D. Robinson, M.D., Professor of Rheumatology at the University of Michigan School of Medicine. Dr. Fox’s research focuses on defining and characterizing pathways of human T cell activation, determining the role of these pathways in the pathogenesis of autoimmune disease, investigating T

cell interactions with synovial fibroblasts, understanding the role of IL-17 in arthritis, and exploring novel approaches to the treatment of rheumatoid arthritis and scleroderma. He is a member of the American Society for Clinical Investigation and the Association of American Physicians. Dr. Fox previously served as an Associate Editor for the JCI (1997–2002).

Publication highlights in this issue Wu Q, Mills EA, Wang Q, Dowling CA, Fisher C, Kirch B, Lundy SK, Fox DA, Mao-Draayer Y. Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis. JCI Insight. 2020;5(3):e134251.

Khanna D, Spino C, Johnson S, Chung L, Whitfield ML, Denton CP, Berrocal V, Franks J, Mehta B, Molitor J, Steen VD, Lafyatis R, Simms RW, Gill A, Kafaja S, Frech TM, Hsu V, Domsic RT, Pope JE, Gordon JK, Mayes MD, Schiopu E, Young A, Sandorfi N, Park J, Hant FN, Bernstein EJ, Chatterjee S, Castelino FV, Ajam A, Wang Y, Wood T, Allanore Y, Matucci-Cerinic M, Distler O, Singer O, Bush E, Fox DA, Furst DE. Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol. 2020;72(1):125–136.

Du Y, Lu C, Morgan RL, Stinson WA, Campbell PL, Cealey E, Fu W, Lepore NJ, Hervoso JL, Cui H, Urquhart AG, Lawton JN, Chung KC, Fox DA, Amin MA. Angiogenic and arthritogenic properties of the soluble form of CD13. J Immunol. 2019;203(2):360–369.

Carmona-Rivera C, Carlucci PM, Moore E, Lingampalli N, Uchtenhagen H, James E, Liu Y, Bicker KL, Wahamaa H, Hoffmann V, Catrina AI, Thompson P, Buckner JH, Robinson WH, Fox DA, Kaplan MJ. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol. 2017;2(10):eaag3358.

Li Y, Singer NG, Whitbred J, Bowen MA, Fox DA, Lin F. CD6 as a potential target for treating multiple sclerosis. Proc Natl Acad Sci U S A. 2017;114(10):2687–2692.

Morgan RL, Behbahani-Nejad N, Endres J, Amin MA, Lepore NJ, Du Y, Urquhart A, Chung KC, Fox DA. Localization, shedding, regulation and function of aminopeptidase N/CD13 on fibroblast like synoviocytes. PLoS One. 2016;11(9):e0162008.

JCI Insight’s Editorial Board is composed of peer scientists at the University of Michigan and the University of Pennsylvania. Members of the Editorial Board review and oversee the peer review process of manuscripts directly submitted to JCI Insight, evaluate all transferred manuscripts, and meet weekly to discuss manuscripts under review.

Featured Editor

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 011

Editor’s picks

on the jci insight cover immunology

Kidney-resident Treg populations influence outcome after renal injuryPatients with acute kidney injury (AKI) are at high risk of chronic kidney disease (CKD) and end-stage renal failure. The drivers of the AKI-to-CKD transition are not fully understood, though immune cell function changes have been implicated. Fernanda do Valle Duraes and colleagues profiled changes in immune cell composition and transcription profiles in two murine models of AKI, one of which results in full regeneration and one of which progresses to fibrosis and CKD. In both models, kidney-resident Treg populations expanded in response to injury but had distinct expression profiles, with angiogenesis and repair genes upregulated in Tregs from the regenerative model and fibrotic, inflammatory, and apoptotic genes elevated in Tregs from the CKD model. Moreover, expansion of resident Tregs with IL-2 and IL-33 prior to injury was protective against AKI. These results reveal a heterogeneity and plasticity in the kidney-resident Treg population that influences injury outcome. The cover image shows 9 distinct clusters of resident and infiltrating immune cell populations present in normal, regenerating, and fibrotic kidneys.

Immune cell landscaping reveals a protective role for regulatory T cells during kidney injury and fibrosisFernanda do Valle Duraes, Armelle Lafont, Martin Beibel, Kea Martin, Katy Darribat, Rachel Cuttat, Annick Waldt, Ulrike Naumann, Grazyna Wieczorek, Swann Gaulis, Sabina Pfister, Kirsten D. Mertz, Jianping Li, Guglielmo Roma, and Max Warncke http://jci.me/130651

Persistence of measles virus RNA promotes long-term humoral immunityAlthough the live attenuated measles vaccine is very effective, its protection can wane over time, resulting in secondary vaccine failure. In contrast, recovery from measles infection induces lifelong immunity from the virus. Ashley Nelson and colleagues investigated the mechanism underlying this long-term immunity in a rhesus macaque model. Measles virus RNA was rarely detected in the bone marrow but persisted in lymphoid cells for 6 months after infection, and measles virus–specific antibody- secreting cells were detectable for the duration of the study. Infection led to long-term presence of germinal centers, and a population of measles virus–specific T follicular helper cells that was sustained over at least 4

months. Therefore, the lifelong protective immunity to measles is due to persistent viral RNA and protein within lymphoid tissue, which promotes prolonged maturation and maintenance of the measles-neutralizing antibody response.

Association of persistent wild-type measles virus RNA with long-term humoral immunity in rhesus macaquesAshley N. Nelson, Wen-Hsuan W. Lin, Rupak Shivakoti, Nicole E. Putnam, Lisa Mangus, Robert J. Adams, Debra Hauer, Victoria K. Baxter, and Diane E. Griffin (ASCI) http://jci.me/134992

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0

JCI Insight | Editor’s picks

12

hepatology

Idiopathic inflammatory myopathy etiology linked to neutrophil dysfunction

Argininosuccinate lyase deficiency linked to impaired hepatic glycogen metabolism

autoimmunity

Idiopathic inflammatory myopathies (IIM) are autoimmune conditions characterized by muscle inflammation and weakness, myositis-specific autoantibodies (MSAs), and extramuscular organ damage. In other autoimmune conditions, neutrophils have been found to play important pathogenic roles, in particular due to their production of neutrophil extracellular traps (NETs), which are

sources of autoantigens and immunostimulatory molecules. However, the function of neutrophils in IIM has not been determined. Nickie Seto and colleagues investigated the presence of pathogenic neutrophils and NET formation in cohorts of patients with IIM, and found that both were increased in the disease setting and correlated with disease severity. The level of myositis-specific autoantibody

anti-MDA5 correlated with NETs in patients with IIM, and anti-MDA5 directly promoted NET formation by neutrophils in vitro (see the accompanying image). Furthermore, an enhanced neutrophil gene signature was associated with muscle injury in tissue from patients with IIM. Importantly, NETs could directly harm skeletal muscle cells, further supporting a pathogenic role of neutrophils in IIM.

Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathiesNickie Seto, Jose Jiram Torres-Ruiz, Carmelo Carmona-Rivera, Iago Pinal-Fernandez, Katherine Pak, Monica M. Purmalek, Yuji Hosono, Catia Fernandes-Cerqueira, Prateek Gowda, Nathan Arnett, Alexander Gorbach, Olivier Benveniste, Diana Gómez-Martín, Albert Selva-O’Callaghan, José C. Milisenda, Josep M. Grau-Junyent, Lisa Christopher-Stine, Frederick W. Miller, Ingrid E. Lundberg, J. Michelle Kahlenberg, Adam I. Schiffenbauer, Andrew Mammen, Lisa G. Rider, and Mariana J. Kaplan (ASCI) http://jci.me/134189

Urea cycle disorders, including argininosuccinate lyase deficiency (ASLD), are associated with hepatic complica-tions, but the mechanisms underlying this connection are unclear. Lindsay Burrage, Simran Madan, and colleagues analyzed data from a longitudinal study of patients with urea cycle disorders and demonstrated a high prevalence of elevated serum alanine aminotransferase (ALT) in ASLD patients. However, ultrasound and other clinical assessments revealed hepatic dysfunction even in patients with normal ALT, indicating that hepatic aminotransferase levels may be insufficient to fully identify hepatic complications. In an ASL-deficient mouse model, the chronic hepatocellular injury observed in patients was present, as indicated by increased serum ALT levels and excessive hepatic glycogen deposition (see the accompanying image) due to decreased glycogenoly-sis. In this model, the glycogen deposition phenotype was

rescued by liver-specific adenoviral expression of ASL. These data link urea cycle dysfunction and impaired hepatic glucose metabolism, and they support the ASLD mouse model as an important tool for studies of liver disease associated with urea cycle dysfunction.

Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiencyLindsay C. Burrage, Simran Madan, Xiaohui Li, Saima Ali, Mahmoud Mohammad, Bridget M. Stroup, Ming-Ming Jiang, Racel Cela, Terry Bertin, Jian Dai, Danielle Guffey, Milton Finegold, Members of the Urea Cycle Disorders Consortium (UCDC), Sandesh Nagamani, Charles G. Minard, Juan Marini, Prakash Masand, Deborah Schady, Benjamin L. Shneider, Daniel H. Leung, Deeksha Bali, and Brendan Lee (ASCI) http://jci.me/132342

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 013

JCI Insight | Editor’s picks

reproductive biology hematology

Alterations in progenitor cell populations characterized in bone marrow failureAlthough cytogenic abnormalities and point mutations have been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the mechanisms that drive clonal hematopoiesis in these patients are poorly understood. Patients with inherited bone marrow failure syndromes (IBMFSs) have a high risk of progressing to MDS and AML and thus provide an opportunity to study the mechanisms driving disease. Stephanie Heidemann, Brian Bursic, and colleagues performed immunophenotyping of patients with 2 forms of IBMFS and showed that they had greatly reduced numbers of hematopoietic stem and progenitor cells but selective preservation of a granulocyte-monocyte progenitor–like (GMP-like) population. Sequencing of the GMP-like cells revealed a high mutational burden and specifically changes that are similar to those described for AML. In sequential samples from a patient with IBMFS who developed AML, the number of mutations in GMP-like cells grew in concert with disease progression. Taken together, these data indicate that GMP-like cells may serve as a reservoir for clonal evolution in hematopoietic disorders.

Cellular and molecular architecture of hematopoietic stem cells and progenitors in genetic models of bone marrow failureStephanie Heidemann, Brian Bursic, Sasan Zandi, Hongbing Li, Sagi Abelson, Robert J. Klaassen, Sharon Abish, Meera Rayar, Vicky R. Breakey, Houtan Moshiri, Santhosh Dhanraj, Richard de Borja, Adam Shlien, John E. Dick, and Yigal Dror http://jci.me/131018

Drug repositioning identifies candidates for preterm birth preventionPreterm birth is the leading cause of infant mortality worldwide. In late pregnancy, the immune system becomes proinflammatory to promote labor, and preterm birth may result from early induction of this change. Brian Le and colleagues searched for drugs with the potential to prevent a premature upregulation of innate immune pathways. Specifically, a transcriptomic drug repositioning approach was applied to identify FDA-approved drugs that alter gene expression profiles in the direction opposite to that observed in the immune system of women who delivered preterm. Progesterone, the only FDA-approved drug used to prevent preterm birth, was among the therapeutic predictions. Analysis of proteins that interact with the drug hits enabled construction of a network of shared interactions. In an inflammatory mouse model of pregnancy loss, administration of one of the identified drugs, lansopra-zole, increased the number of viable fetuses. This work supports transcriptomic drug repositioning to identify additional uses for FDA-approved drugs and demonstrates the therapeutic potential of lansoprazole to prevent preterm birth.

Computational discovery of therapeutic candidates for preventing preterm birthBrian L. Le, Sota Iwatani, Ronald J. Wong, David K. Stevenson, and Marina Sirota http://jci.me/133761

PTIP-mediated epigenetic modifications promote repair after kidney injury

nephrology

Mature, terminally differentiated cells are thought to maintain their phenotype, in part, through histone modifications. In the setting of injury, some terminally differentiated cells can reenter the cell cycle and acquire markers of dedifferentiated, more embryonic- like cells, but whether epigenetic mechanisms are required to reestablish the phenotype of regenerated cells is unclear. To address this question, Abdul Soofi and colleagues studied the role of PTIP, a component of the complex that confers histone H3 lysine 4 (H3K4) methylation, in kidney regeneration. Mice lacking PTIP in the proximal tubule exhibited normal kidney function at baseline. However, when subjected to acute kidney injury, PTIP-deficient cells failed to

reenter mitosis, compromising repair and repopula-tion (see accompanying image). These findings indicate that reduced levels of H3K4 methylation impact the capacity for regeneration, and they suggest that de novo histone methylation is required to reset the epigenome of regenerated cells.

Regeneration after acute kidney injury requires PTIP-mediated epigenetic modificationsAbdul Soofi, Ana P. Kutschat, Mohammad Azam, Ann M. Laszczyk, and Gregory R. Dressler http://jci.me/130204

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0 14

Current articles

Cardiac TRPV1 afferent signaling promotes arrhythmogenic ventricular remodeling after myocardial infarctionKoji Yoshie, Pradeep S. Rajendran, Louis Massoud, Janki Mistry, M. Amer Swid, Xiaohui Wu, Tamer Sallam, Rui Zhang, Joshua I. Goldhaber, Siamak Salavatian, and Olujimi A. Ajijola http://jci.me/124477

SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetesTao Liang, Tairan Qin, Fei Kang, Youhou Kang, Li Xie, Dan Zhu, Subhankar Dolai, Dafna Greitzer-Antes, Robert K. Baker, Daorong Feng, Eva Tuduri, Claes-Goran Ostenson, Timothy J. Kieffer, Kate Banks, Jeffrey E. Pessin, and Herbert Y. Gaisano http://jci.me/129694

Regeneration after acute kidney injury requires PTIP-mediated epigenetic modifications p. 13Abdul Soofi, Ana P. Kutschat, Mohammad Azam, Ann M. Laszczyk, and Gregory R. Dressler http://jci.me/130204

Immune cell landscaping reveals a protective role for regulatory T cells during kidney injury and fibrosis p. 11Fernanda do Valle Duraes, Armelle Lafont, Martin Beibel, Kea Martin, Katy Darribat, Rachel Cuttat, Annick Waldt, Ulrike Naumann, Grazyna Wieczorek, Swann Gaulis, Sabina Pfister, Kirsten D. Mertz, Jianping Li, Guglielmo Roma, and Max Warncke http://jci.me/130651

Autoimmune inner ear disease patient–associated 28-kDa proinflammatory IL-1β fragment results from caspase-7–mediated cleavage in vitroShresh Pathak and Andrea Vambutas http://jci.me/130845

Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in miceJun Xu, Hsiao-Yen Ma, Xiao Liu, Sara Rosenthal, Jacopo Baglieri, Ryan McCubbin, Mengxi Sun, Yukinori Koyama, Cedric G. Geoffroy, Kaoru Saijo, Linshan Shang, Takahiro Nishio, Igor Maricic, Max Kreifeldt, Praveen Kusumanchi, Amanda Roberts, Binhai Zheng, Vipin Kumar, Karsten Zengler, Donald P. Pizzo, Mojgan Hosseini, Candice Contet, Chris K. Glass, Suthat Liangpunsakul, Hidekazu Tsukamoto, Bin Gao, Michael Karin, David A. Brenner, George F. Koob, and Tatiana Kisseleva http://jci.me/131277

Endothelial cell–glucocorticoid receptor interactions and regulation of Wnt signalingHan Zhou, Sameet Mehta, Swayam Prakash Srivastava, Kariona Grabinska, Xinbo Zhang, Chris Wong, Ahmad Hedayat, Paola Perrotta, Carlos Fernández-Hernando, William C. Sessa, and Julie E. Goodwin http://jci.me/131384

GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signalingWen-Lian Chen, Xing Jin, Mingsong Wang, Dan Liu, Qin Luo, Hechuan Tian, Lili Cai, Lifei Meng, Rui Bi, Lei Wang, Xiao Xie, Guanzhen Yu, Lihui Li, Changsheng Dong, Qiliang Cai, Wei Jia, Wenyi Wei, and Lijun Jia http://jci.me/131596

Microglial depletion under thalamic hemorrhage ameliorates mechanical allodynia and suppresses aberrant axonal sproutingShin-ichiro Hiraga, Takahide Itokazu, Maki Hoshiko, Hironobu Takaya, Mariko Nishibe, and Toshihide Yamashita http://jci.me/131801

Dnmt3b ablation impairs fracture repair through upregulation of Notch pathwayJun Ying, Taotao Xu, Cuicui Wang, Hongting Jin, Peijian Tong, Jianjun Guan, Yousef Abu-Amer, Regis O’Keefe, and Jie Shen http://jci.me/131816

Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathiesJolien Wolbert, Mandy I. Cheng, Gerd Meyer zu Horste, and Maureen A. Su (ASCI) http://jci.me/132411

Targeting IL-17A/glucocorticoid synergy to CSF3 expression in neutrophilic airway diseasesSuidong Ouyang, Caini Liu, Jianxin Xiao, Xing Chen, Andy C. Lui, and Xiaoxia Li http://jci.me/132836

Ultrasound-induced microbubble cavitation via a transcanal or transcranial approach facilitates inner ear drug deliveryAi-Ho Liao, Chih-Hung Wang, Ping-Yu Weng, Yi-Chun Lin, Hao Wang, Hang-Kang Chen, Hao-Li Liu, Ho-Chiao Chuang, and Cheng-Ping Shih http://jci.me/132880

Notch controls urothelial integrity in the mouse bladderVarvara Paraskevopoulou, Vangelis Bonis, Vasilis S. Dionellis, Nikolaos Paschalidis, Pelagia Melissa, Evangelia Chavdoula, Eleni Vasilaki, Ioannis S. Pateras, and Apostolos Klinakis http://jci.me/133232

Kisspeptin enhances brain responses to olfactory and visual cues of attraction in menLisa Yang, Lysia Demetriou, Matthew B. Wall, Edouard G.A. Mills, David Zargaran, Mark Sykes, Julia K. Prague, Ali Abbara, Bryn M. Owen, Paul A. Bassett, Eugenii A. Rabiner, Alexander N. Comninos, and Waljit S. Dhillo http://jci.me/133633

The RNFT2/IL-3Rα axis regulates IL-3 signaling and innate immunityYao Tong, Travis B. Lear, John Evankovich, Yanwen Chen, James D. Londino, Michael M. Myerburg, Yingze Zhang, Iulia D. Popescu, John F. McDyer, Bryan J. McVerry, Karina C. Lockwood, Michael J. Jurczak, Yuan Liu, and Bill B. Chen http://jci.me/133652

Reciprocal immune enhancement of dengue and Zika virus infection in human skinPriscila M. S. Castanha, Geza Erdos, Simon C. Watkins, Louis D. Falo Jr., Ernesto T. A. Marques, and Simon M. Barratt-Boyes http://jci.me/133653

Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies p. 12Nickie Seto, Jose Jiram Torres-Ruiz, Carmelo Carmona-Rivera, Iago Pinal Fernandez, Katherine Pak, Monica M. Purmalek, Yuji Hosono, Catia Fernandes-Cerqueira, Prateek Gowda, Nathan Arnett, Alexander Gorbach, Olivier Benveniste, Diana Gómez-Martín, Albert Selva-O’Callaghan, José C. Milisenda, Josep M. Grau-Junyent, Lisa Christopher-Stine, Frederick W. Miller, Ingrid Lundberg, J. Michelle Kahlenberg, Adam I. Schiffenbauer, Andrew Mammen, Lisa G. Rider, and Mariana J. Kaplan (ASCI) http://jci.me/134189

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 015

Current articles

Computational discovery of therapeutic candidates for preventing preterm birth p. 13Brian L. Le, Sota Iwatani, Ronald J. Wong, David K. Stevenson, and Marina Sirota http://jci.me/133761

Stiff matrix instigates type I collagen biogenesis by mammalian cleavage factor I complex-mediated alternative polyadenylationZijing Zhou, Jing Qu, Li He, Yi Zhu, Shan-Zhong Yang, Feng Zhang, Ting Guo, Hong Peng, Ping Chen, and Yong Zhou http://jci.me/133972

Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohortWilliam Z. Zhang, Michelle C. Rice, Katherine L. Hoffman, Clara Oromendia, Igor Z. Barjaktarevic, J. Michael Wells, Annette T. Hastie, Wassim W. Labaki, Christopher B. Cooper, Alejandro P. Comellas, Gerard J. Criner, Jerry A. Krishnan, Robert Paine III, Nadia N. Hansel, Russell P. Bowler, R. Graham Barr, Stephen P. Peters, Prescott G. Woodruff, Jeffrey L. Curtis, Meilan K. Han, Karla V. Ballman, Fernando J. Martinez, Augustine M.K. Choi, Kiichi Nakahira, Suzanne M. Cloonan, Mary E. Choi, and the SPIROMICS Investigators http://jci.me/133984

Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosisQi Wu, Elizabeth A. Mills, Qin Wang, Catherine A. Dowling, Caitlyn Fisher, Britany Kirch, Steven K. Lundy, David A. Fox, Yang Mao-Draayer, and the AMS04 Study Group http://jci.me/134251

Circadian rhythm phase shifts caused by timed exercise vary with chronotypeJ. Matthew Thomas, Philip A. Kern (ASCI), Heather M. Bush, Kristen J. McQuerry, W. Scott Black, Jody L. Clasey, and Julie S. Pendergast http://jci.me/134270

Myocardial B cells are a subset of circulating lymphocytes with delayed transit through the heartLuigi Adamo, Cibele Rocha-Resende, Chieh-Yu Lin, Sarah Evans, Jesse Williams, Hao Dun, Wenjun Li, Cedric Mpoy, Prabhakar S. Andhey, Buck E. Rogers, Kory Lavine, Daniel Kreisel, Maxim Artyomov, Gwendalyn J. Randolph, and Douglas L. Mann (ASCI) http://jci.me/134700

Association of persistent wild-type measles virus RNA with long-term humoral immunity in rhesus macaques p. 11Ashley N. Nelson, Wen-Hsuan W. Lin, Rupak Shivakoti, Nicole E. Putnam, Lisa Mangus, Robert J. Adams, Debra Hauer, Victoria K. Baxter, and Diane E. Griffin (ASCI) http://jci.me/134992

Integrated, multicohort anal66ysis reveals unified signature of systemic lupus erythematosusWinston A. Haynes, D. James Haddon, Vivian K. Diep, Avani Khatri, Erika Bongen, Gloria Yiu, Imelda Balboni, Christopher R. Bolen, Rong Mao, Paul J. Utz, and Purvesh Khatri http://jci.me/122312

FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosisJack Leslie, Ben J.M. Millar, Alicia del Carpio Pons, Rachel A. Burgoyne, Joseph D. Frost, Ben S. Barksby, Saimir Luli, Jon Scott, A. John Simpson, Jack Gauldie, Lynne A. Murray, Donna K. Finch, Alan M. Carruthers, John Ferguson, Matthew A. Sleeman, David Rider, Rachel Howarth, Christopher Fox, Fiona Oakley, Andrew J. Fisher, Derek A. Mann, and Lee A. Borthwick http://jci.me/125937

Genetic modification increases the survival and the neuroregenerative properties of transplanted neural stem cellsIrina Korshunova, Sina Rhein, Diego García-González, Ines Stölting, Ulrich Pfisterer, Anna Barta, Oksana Dmytriyeva, Agnete Kirkeby, Markus Schwaninger, and Konstantin Khodosevich http://jci.me/126268

Alcohol exposure–induced neurovascular inflammatory priming impacts ischemic stroke and is linked with brain perivascular macrophagesAntoine Drieu, Anastasia Lanquetin, Damien Levard, Martina Glavan, Francisco Campos, Aurélien Quenault, Eloïse Lemarchand, Mikaël Naveau, Anne Lise Pitel, José Castillo, Denis Vivien, and Marina Rubio http://jci.me/129226

Fibroblast subtypes define a metastatic matrisome in breast cancerHeather M. Brechbuhl, Alexander S. Barrett, Etana Kopin, Jaime C. Hagen, Amy L. Han, Austin E. Gillen, Jessica Finlay-Schultz, Diana M. Cittelly, Philip Owens, Kathryn B. Horwitz, Carol A. Sartorius, Kirk Hansen, and Peter Kabos http://jci.me/130751

Cellular and molecular architecture of hematopoietic stem cells and progenitors in genetic models of bone marrow failure p. 13Stephanie Heidemann, Brian Bursic, Sasan Zandi, Hongbing Li, Sagi Abelson, Robert J. Klaassen, Sharon Abish, Meera Rayar, Vicky R. Breakey, Houtan Moshiri, Santhosh Dhanraj, Richard de Borja, Adam Shlien, John E. Dick, and Yigal Dror http://jci.me/131018

Arp2/3 inactivation causes intervertebral disc and cartilage degeneration with dysregulated TonEBP-mediated osmoadaptationSteven Tessier, Alexandra C. Doolittle, Kimheak Sao, Jeremy D. Rotty, James E. Bear, Veronica Ulici, Richard F. Loeser, Irving M. Shapiro, Brian O. Diekman, and Makarand V. Risbud http://jci.me/131382

Urinary cell transcriptomics and acute rejection in human kidney allograftsAkanksha Verma, Thangamani Muthukumar, Hua Yang, Michelle Lubetzky, Michael F. Cassidy, John R. Lee, Darshana M. Dadhania, Catherine Snopkowski, Divya Shankaranarayanan, Steven P. Salvatore, Vijay Sharma, Jenny Xiang, Iwijn De Vlaminck, Surya Seshan, Franco B. Mueller, Karsten Suhre, Olivier Elemento, and Manikkam Suthanthiran (ASCI) http://jci.me/131552

Dlx1/2 mice have abnormal enteric nervous system functionChristina M. Wright , James P. Garifallou, Sabine Schneider, Heather L. Mentch, Deepika R. Kothakapa, Beth A. Maguire, and Robert O. Heuckeroth (ASCI) http://jci.me/131494

j c i . o r g / t h i s - m o n t h m a r c h 2 0 2 0

Regnase-1 degradation is crucial for IL-33– and IL-25–mediated ILC2 activationKazufumi Matsushita, Hiroki Tanaka, Koubun Yasuda, Takumi Adachi, Ayumi Fukuoka, Shoko Akasaki, Atsuhide Koida, Etsushi Kuroda, Shizuo Akira, and Tomohiro Yoshimoto http://jci.me/131480

MAPK mutations and cigarette smoke promote the pathogenesis of pulmonary Langerhans cell histiocytosisHuan Liu, Andrew R. Osterburg, Jennifer Flury, Zulma Swank, Dennis W. McGraw, Nishant Gupta, Kathryn A. Wikenheiser-Brokamp, Ashish Kumar, Abdellatif Tazi, Yoshikazu Inoue, Masaki Hirose, Francis X. McCormack (ASCI), and Michael Borchers http://jci.me/132048

Rescuing compounds for Lesch-Nyhan disease identified using stem cell–based phenotypic screeningValentin Ruillier, Johana Tournois, Claire Boissart, Marie Lasbareilles, Gurvan Mahé, Laure Chatrousse, Michel Cailleret, Marc Peschanski, and Alexandra Benchoua http://jci.me/132094

Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency p. 12Lindsay C. Burrage, Simran Madan, Xiaohui Li, Saima Ali, Mahmoud Mohammad, Bridget M. Stroup, Ming-Ming Jiang, Racel Cela, Terry Bertin, Jian Dai, Danielle Guffey, Milton Finegold, Members of the Urea Cycle Disorders Consortium (UCDC), Sandesh Nagamani, Charles G. Minard, Juan Marini, Prakash Masand, Deborah Schady, Benjamin L. Shneider, Daniel H. Leung, Deeksha Bali, and Brendan Lee (ASCI) http://jci.me/132342

Differential decay of intact and defective proviral DNA in HIV-1–infected individuals on suppressive antiretroviral therapyMichael J. Peluso, Peter Bacchetti, Kristen D. Ritter, Subul A. Beg, Jun Lai, Jeffrey N. Martin, Peter W. Hunt, Timothy J. Henrich, Janet D. Siliciano, Robert F. Siliciano, Gregory M. Laird, and Steven G. Deeks (ASCI) http://jci.me/132997

Pneumonia recovery reprograms the alveolar macrophage poolAntoine Guillon, Emad I. Arafa, Kimberly A. Barker, Anna C. Belkina, Ian M.C. Martin, Anukul T. Shenoy, Alicia K. Wooten, Carolina Lyon De Ana, Anqi Dai, Adam Labadorf, Jaileene Hernandez-Escalante, Hans Dooms, Helene Blasco, Katrina E. Traber, Matthew R. Jones, Lee J. Quinton, and Joseph P. Mizgerd http://jci.me/133042

IL-4 induces M2 macrophages to produce sustained analgesia via opioidsMelih Ö. Celik, Dominika Labuz, Jacqueline Keye, Rainer Glauben, and Halina Machelska http://jci.me/133093

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiationTeresa Preglej, Patricia Hamminger, Maik Luu, Tanja Bulat, Liisa Andersen, Lisa Göschl, Valentina Stolz, Ramona Rica, Lisa Sandner, Darina Waltenberger, Roland Tschismarov, Thomas Faux, Thorina Boenke, Asta Lahio, Laura L. Elo, Shinya Sakaguchi, Güenter Steiner, Thomas Decker, Barbara Bohle, Alexander Visekruna, Christoph Bock, Birgit Strobl, Christian Seiser, Nicole Boucheron, and Wilfried Ellmeier http://jci.me/133393

TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumorsNa Tang, Chen Cheng, Xingying Zhang, Miaomiao Qiao, Na Li, Wei Mu, Xiao-Fei Wei, Weidong Han, and Haoyi Wang http://jci.me/133977

EMRE is essential for mitochondrial calcium uniporter activity in a mouse modelJulia C. Liu, Nicole C. Syder, Nima S. Ghorashi, Thomas B. Willingham, Randi J. Parks, Junhui Sun, Maria M. Fergusson, Jie Liu, Kira M. Holmström, Sara Menazza, Danielle A. Springer, Chengyu Liu, Brian Glancy, Toren Finkel, and Elizabeth Murphy http://jci.me/134063

Differences in inducibility latent HIV reservoir in perinatal and adult infectionAdit Dhummakupt, Jessica H. Rubens, Thuy Anderson, Laura Powell, Bareng A.S. Nonyane, Lilly V. Siems, Aleisha Collinson-Streng, Tricia L. Nilles, R. Brad Jones, Vicki Tepper, Allison Agwu, and Deborah Persaud http://jci.me/134105

Immune cell repertoires in breast cancer patients after adjuvant chemotherapyClaire E. Gustafson, Rohit R. Jadhav, Wenqiang Cao, Qian Qi, Mark Pegram, Lu Tian, Cornelia M. Weyand, and Jörg J. Goronzy (ASCI) http://jci.me/134569

Identification of Alzheimer’s disease–associated rare coding variants in the ECE2 geneXinxin Liao, Fang Cai, Zhanfang Sun, Yun Zhang, Juelu Wang, Bin Jiao, Jifeng Guo, Jinchen Li, Xixi Liu, Lina Guo, Yafang Zhou, Junling Wang, Xinxiang Yan, Hong Jiang, Kun Xia, Jiada Li, Beisha Tang, Lu Shen, and Weihong Song http://jci.me/135119

Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancyAllison L. Fisher, Veena Sangkhae, Pietro Presicce, Claire A. Chougnet, Alan H. Jobe, Suhas G. Kallapur, Sammy M. Tabbah, Catalin S. Buhimschi, Irina A. Buhimschi, Tomas Ganz, and Elizabeta Nemeth http://jci.me/135321

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesisSonu Kashyap, Kyaw Zaw Hein, Claudia C.S. Chini, Jorgo Lika, Gina M. Warner, Laurie K. Bale, Vicente E. Torres, Peter C. Harris, Claus Oxvig, Cheryl A. Conover, and Eduardo N. Chini http://jci.me/135700

perspectiveMind the gap: Expediting gender parity in MD-PhD admissionsTemperance R. Rowell, Robert A. Redd, Donna S. Neuberg, and Loren D. Walensky (ASCI) http://jci.me/136037

16

Flip issue to read JCI content.