jci.org/this-month

Myeloid-derived suppressor cells regulate inflammation in newborns 2

Characterizing genetic variation in β cell function 3

Immune landscape of immunotherapy-induced pneumonitis 4

E-cigarette vapors compromise lung immunity 5

Review Series:Mechanisms Underlying the Metabolic Syndrome edited by Philipp E. Scherer 6

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.

October 2019

Targeting APOC3 prevents diabetes-associated atherogenesis p. 2

This Month

Journal of Clinical Investigation Consulting Editors

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David James

Richard J. Jones

William G. Kaelin Jr.

Klaus Kaestner

Mark L. Kahn

Raghu Kalluri

S. Ananth Karumanchi

David A. Kass

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Masato Kasuga

Daniel P. Kelly

Dontscho Kerjaschki

Sundeep Khosla

Richard N. Kitsis

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Jay K. Kolls

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Stavroula Kousteni

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Rohit N. Kulkarni

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Antonio La Cava

Fadi G. Lakkis

Terri Laufer

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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

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Steven O. Marx

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Elizabeth McNally

Cornelis J. Melief

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George Michalopoulos

Jeffrey H. Miner

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Anthony J. Muslin

Martin G. Myers Jr.

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Catherine Postic

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Louis J. Ptáček

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Pere Puigserver

Bali Pulendran

Ellen Puré

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Daniel J. Rader

Shahin Rafii

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W. Kimryn Rathmell

Barbara Rehermann

Muredach P. Reilly

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

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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

Kang Zhang

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j c i . o r g / t h i s - m o n t h o c t o b e r 2 0 1 9 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

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Staff EditorsExecutive EditorSarah C. Jackson

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JCI This Month ISSN 2324-7703 (print);ISSN 2325-4556 (online)

For the full JCI online: jci.me/129/10

This MonthOctober 2019

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)

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(ASCI) indicates corresponding authors who are ASCI members.

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

Mark Anderson, MD, PhD, Associ-ate Editor, is William Osler Professor of Medicine and Director of the Depart-ment of Medicine at Johns Hopkins University and Physician-in-Chief of the Johns Hopkins Hospital. Dr. Anderson’s research is focused on cellular signaling and ionic mechanisms that cause heart failure and sudden cardiac death, and defining the role of calmodulin kinase II regulation in heart failure and arrhyth-mias. He is a member of the American Society for Clinical Investigation, the Association of American Physicians, the American Clinical and Climatological Association, and the Fondation Leducq Scientific Advisory Committee.

Publication highlights

Wu Y, Wang Q, Feng N, Granger JM, Anderson ME. Myocardial death and dys-function after ischemia-reperfusion injury require CaMKIIδ oxidation. Sci Rep. 2019;9(1):9291.

Lehman SJ, Tal-Grinspan L, Lynn ML, Strom J, Benitex GE, Anderson ME, Tar-diff JC. Chronic calmodulin-kinase II activation drives disease progression in mutation-specific hypertrophic cardiomyopathy. Circulation. 2019;139(12):1517–1529.

Guo A, Wang Y, Chen B, Wang Y, Yuan J, Zhang L, Hall D, Wu J, Shi Y, Zhu Q, Chen C, Thiel WH, Zhan X, Weiss RM, Zhan F, Musselman CA, Pufall M, Zhu W, Au KF, Hong J, Anderson ME, Grueter CE, Song LS. E-C coupling struc-tural protein junctophilin-2 encodes a stress-adaptive transcription regulator. Science. 2018;362(6421):eaan3303.

Qu J, Do DC, Zhou Y, Luczak E, Mitzner W, Anderson ME, Gao P. Oxidized CaMKII promotes asthma through the activation of mast cells. JCI Insight. 2017;2(1):e90139.

j c i . o r g / t h i s - m o n t h o c t o b e r 2 0 1 92

research

Editor’s picks

on the jci cover metabolism

immunology

Lactoferrin-induced MDSC therapy controls pathologic inflammation in newborn miceMyeloid-derived suppressor cells (MDSCs) play an important role in controlling infection and pathological inflammation in newborns. However, MDSC function remains unclear in preterm infants, who are at increased risk for inflammatory conditions, such as necrotizing colitis (NEC). Yufeng Liu and colleagues observed that preterm infants had lower MDSC levels at birth than full-term infants and that those with the lowest levels were more likely to develop NEC. Both preterm birth and NEC development were associated with lower levels of lactoferrin, a component of human and cow milk. Lactoferrin exposure induced neutrophil and monocyte conversion to MDSCs in cells derived from newborn mice. The conversion required expression of the LRP2 receptor and produced MDSCs with robust immunosuppres-

Targeting apolipoprotein C3 prevents accelerated atherogenesis in insulin-deficient diabetes

The risk of developing atherosclerosis and cardiovascular disease is greater in patients with type 1 diabetes mellitus (T1DM), and hyperglycemia alone does not appear to account for this increased

risk. Because T1DM is not typically associated with aberrant plasma lipids, the roles of lipoprotein-regulating proteins such as apolipoprotein C3 (APOC3) have been relatively unexplored in this disease. In this issue of the JCI,Jenny Kanter et al. evaluated a cohort of 181 patients with T1DM and observed that elevated serum APOC3 levels are a strong predictor of coronary artery disease incidents. APOC3 levels were similarly increased in insulin-deficient diabetic mouse models. Intensive insulin therapy mitigated elevations in APOC3, but the effect was not simply due to normalizing glycemia: an APOC3-targeting antisense oligonucleotide (ASO) produced reductions in plasma triglycerides in diabetic mice without improving glycemic control. Further, the ASO treatment blocked accelerated atherogenesis in these mice. In the accompanying Commentary, Henry Ginsberg and Gissette Reyes-Soffer discuss the potential for selective APOC3 targeting to combat elevated cardiovascular disease risk in patients with T1DM. On the cover, a mouse atherosclerotic lesion (Movat’s

pentachrome stain), an ECG trace, and a heart-shaped lipoprotein particle highlight the role of APOC3 in T1DM-linked cardiovascular disease. Image credit: Jenny Kanter and Karin Bornfeldt.

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetesJenny E. Kanter, Baohai Shao, Farah Kramer, Shelley Barnhart, Masami Shimizu-Albergine, Tomas Vaisar, Mark J. Graham, Rosanne M. Crooke, Clarence R. Manuel, Rebecca A. Haeusler, Daniel Mar, Karol Bomsztyk, John E. Hokanson, Gregory L. Kinney, Janet K. Snell-Bergeon, Jay W. Heinecke, and Karin E. Bornfeldt http://jci.me/127308

Related CommentaryIs APOC3 the driver of cardiovascular disease in people with type I diabetes mellitus?Henry N. Ginsberg and Gissette Reyes-Soffer http://jci.me/131333

sive and antibacterial activity. Treating newborn mice with lactoferrin-induced MDSCs protected against experimentally induced lung, liver, and intestinal inflammation. In the accompanying Commentary, Rebekka Weber and Viktor Umansky indicate a potential use for MSDCs in treating inflammatory conditions in preterm infants.

Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn miceYufeng Liu, Michela Perego, Qiang Xiao, Yumei He, Shuyu Fu, Juan He, Wangkai Liu, Xing Li, Yanlai Tang, Xiaoyu Li, Weiming Yuan, Wei Zhou, Fan Wu, Chunhong Jia, Qiliang Cui, George S. Worthen, Erik A. Jensen, Dmitry I. Gabrilovich, and Jie Zhou http://jci.me/128164

Related CommentaryFighting infant infections with myeloid-derived suppressor cellsRebekka Weber and Viktor Umansky http://jci.me/131649

j c i . o r g / t h i s - m o n t h o c t o b e r 2 0 1 9 3

JCI | Research: Editor’s picks

vascular biology

endocrinology

Dengue virus–induced mast cell tryptase mediates vascular leakage and shockThe most severe manifestation of dengue virus (DENV) infection is dengue hemorrhagic fever (DHF), involving vascular leakage that can lead to hypovolemic shock. The mechanisms driving DENV-elicited vascular leakage remain unclear. Building upon evidence that DENV induces mast cell degranulation, Abhay Rathore and colleagues have identified tryptase as a mast cell–derived mediator of DENV-induced vascular permeability. Tryptase disrupted endothelial cell tight junctions in human endothelial cells and induced vascular leakage and shock in a mouse model. Moreover, retrospective analysis correlated tryptase levels with DHF severity in serum from DENV-infected patients. The researchers then showed that nafamostat mesylate, a clinically approved tryptase inhibitor, prevented vascular leakage in DENV-infected mice (see the associated image). In the accompanying Commentary, Anna Durbin highlights the study’s identification of a potential intervention for severe DENV infection.

Dengue virus–elicited tryptase induces endothelial permeability and shockAbhay P.S. Rathore, Chinmay Kumar Mantri, Siti A.B. Aman, Ayesa Syenina, Justin Ooi, Cyril J. Jagaraj, Chi Ching Goh, Hasitha Tissera, Annelies Wilder-Smith, Lai Guan Ng, Duane J. Gubler, and Ashley L. St. John http://jci.me/128426

Related CommentaryDengue vascular leak syndrome: insights into potentially new treatment modalitiesAnna P. Durbin http://jci.me/131170

Genetic variation in insulin secretion capacity in nondiabetic outbred miceSusceptibility to type 2 diabetes (T2D) is primarily determined by genes that influence an individual’s ability to secrete sufficient insulin. Distinguishing a genetic variation’s effect on insulin secretion requires analyses accounting for the complex signals that modify β cell function as well as studies controlling for β cell mass. Mark Keller and colleagues used Diversity Outbred (DO) mice, which have genetic diversity comparable to that of human populations, to model variation in insulin secretion. They measured insulin secretion across seven nutritional and endocrine challenges, revealing

that DO mice exhibit a 1000-fold range in insulin-secreting capacity that can be mapped to shared genetic hotspots. From these hotspots, the researchers focused on three genes (Ptpn18, Hunk, and Zfp148) corresponding to diabetes-associated SNPs in humans, confirming that experimental variation in these genes produces predictable insulin secretion phenotypes. Mark Herman, Jonathan Campbell, and David D’Alessio comment on the implication that genetic variation can be mapped to β cell function to predict T2D risk in nondiabetic individuals in the accompanying Commentary.

Gene loci associated with insulin secretion in islets from nondiabetic miceMark P. Keller, Mary E. Rabaglia, Kathryn L. Schueler, Donnie S. Stapleton, Daniel M. Gatti, Matthew Vincent, Kelly A. Mitok, Ziyue Wang, Takanao Ishimura, Shane P. Simonett, Christopher H. Emfinger, Rahul Das, Tim Beck, Christina Kendziorski, Karl W. Broman, Brian S. Yandell, Gary A. Churchill, and Alan D. Attie http://jci.me/129143

Related CommentaryOne small step for mice, one giant leap for GWAS?Mark A. Herman, Jonathan E. Campbell, and David A. D’Alessio http://jci.me/131650

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JCI | Research: Editor’s picks

clinical medicine

Sirolimus-induced remission in three treatment-refractory idiopathic multicentric Castleman disease patients

Proinflammatory immune landscape predominates in checkpoint inhibitor pneumonitis patientsImmune checkpoint inhibitors (ICIs) are highly efficacious cancer therapies but can induce highly morbid immune-related toxicities, including checkpoint inhibitor pneumonitis (CIP), which presents with hypoxia and lung infiltrates (see the accompanying image). The mechanisms that lead to CIP are largely unknown, curbing efforts to identify predictive or diagnostic biomarkers. Karthik Suresh, Jarushka Naidoo, and colleagues compared bronchoalveolar lavage (BAL) samples from 6 ICI-treated CIP patients and 12 ICI-treated patients without CIP. Their analysis revealed increased activation of proinflammatory CD4+ T cell subsets and decreased Treg phenotypes in the CIP patients. Consistent with this proinflam-matory landscape, cytokine levels were also elevated in CIP patient BAL. These observations form the basis for mechanistic studies of aberrant immune responses in CIP, which may inform strategies to treat immune-related events following ICI therapy.

Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder involving multiple enlarged lymph nodes and dysfunction of multiple organ systems. Though elevated IL-6 is implicated in the pathogenesis of iMCD, up to two-thirds of patients are nonresponsive or refractory to anti–IL-6 therapy. David Fajgenbaum and colleagues examined an array of proteomic, immunological, and cytokine analyses from three treatment-refractory iMCD patients and discovered that elevated CD8+ T cell activation and serum VEGF-A levels were common features of the patients’ disease flares. Further analyses of candidate pathways and compound databases identified increased PI3K/AKT/mTOR signaling as a likely upstream mediator of both aberrant CD8+ T cell activation and elevated VEGF-A. Treatment with the mTOR inhibitor sirolimus induced disease remission in all three patients. In a related Commentary, Robert Stern and Nancy Berliner characterize the findings, which form the basis for a planned clinical trial, as a successful precision medicine approach that could be modeled in other rare diseases.

Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade–refractory idiopathic multicentric Castleman diseaseDavid C. Fajgenbaum, Ruth-Anne Langan, Alberto Sada Japp, Helen L. Partridge, Sheila K. Pierson, Amrit Singh, Daniel J. Arenas, Jason R. Ruth, Christopher S. Nabel, Katie Stone, Mariko Okumura, Anthony Schwarer, Fábio Freire Jose, Nelson Hamerschlak, Gerald B. Wertheim, Michael B. Jordan, Adam D. Cohen, Vera Krymskaya, Arthur Rubenstein, Michael R. Betts, Taku Kambayashi, Frits van Rhee, and Thomas S. Uldrick http://jci.me/126091

Related CommentaryTargeting the mTOR pathway in idiopathic multicentric Castleman diseaseRobert M. Stern and Nancy Berliner (ASCI) http://jci.me/131332

The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitisKarthik Suresh, Jarushka Naidoo, Qiong Zhong, Ye Xiong, Jennifer Mammen, Marcia Villegas de Flores, Laura Cappelli, Aanika Balaji, Tsvi Palmer, Patrick M. Forde, Valsamo Anagnostou, David S. Ettinger, Kristen A. Marrone, Ronan J. Kelly, Christine L. Hann, Benjamin Levy, Josephine L. Feliciano, Cheng-Ting Lin, David Feller-Kopman, Andrew D. Lerner, Hans Lee, Majid Shafiq, Lonny Yarmus, Evan J. Lipson, Mark Soloski, Julie R. Brahmer, Sonye K. Danoff, and Franco D’Alessio http://jci.me/128654

j c i . o r g / t h i s - m o n t h o c t o b e r 2 0 1 9 5

JCI | Research: Editor’s picks

IL-1α/β trigger pathological mucoinflammatory responses in cystic fibrosis airwaysLung disease in cystic fibrosis (CF) is characterized by chronic obstruction of distal airways by hyperconcentrated mucus, with associated inflammation and tissue damage. Although bacterial infections worsen inflammation, preventing infection does not block the development of lung disease, suggesting that intrinsic mediators play a role in CF lung pathology. In this issue, Gang Chen and colleagues reveal that IL-1α and IL-1β, proinflammatory cytokines present in the mucopurulent secretions of CF patients, activate an IL-1R1–mediated epithelial pathway that induces mucin, but not fluid, secretion, producing hyperconcentrated, adhesive mucus on CF airway surfaces. They corroborated this observation in CF lung samples, associating increased mRNA expression of IL-1β and its downstream mediators SPDEF and ERN2 with elevated mucin gene expression. IL-1R1 blockade suppressed the expression of mucins as well as the proinflammatory mediators IL-8, IL-6, and CXCL1. Susan Birket and Steven Rowe’s accompanying Commentary highlights implications of the finding that IL-1α/β signaling via IL-1R contributes to pathological mucoobstruction and inflammation in CF lung disease.

IL-1β dominates the promucin secretory cytokine profile in cystic fibrosisGang Chen, Ling Sun, Takafumi Kato, Kenichi Okuda, Mary B. Martino, Aiman Abzhanova, Jennifer M. Lin, Rodney C. Gilmore, Bethany D. Batson, Yvonne K. O’Neal, Allison S. Volmer, Hong Dang, Yangmei Deng, Scott H. Randell, Brian Button, Alessandra Livraghi-Butrico, Mehmet Kesimer, Carla M.P. Ribeiro, Wanda K. O’Neal, and Richard C. Boucher (ASCI) http://jci.me/125669

Related CommentaryRevealing the molecular signaling pathways of mucus stasis in cystic fibrosisSusan E. Birket and Steven M. Rowe (ASCI) http://jci.me/131652

pulmonology

E-cigarette vapor exposure impairs lung immunity and lipid homeostasisE-cigarettes are often touted as healthier alternatives to conventional cigarettes, relying on solvent vapors rather than tobacco smoke to deliver nicotine. While the solvents used in e-cigarettes are approved as safe food additives, the health consequences of inhaling their vapors remain unknown. Matthew Madison and colleagues compared the immunological effects of long-term vapor and smoke exposure in the lungs of mice. While vapor-exposed mice did not develop the lung pathologies observed in their smoke-exposed counterparts, the researchers observed increased lipid accumulation in alveolar macrophages (AMs) relative to both smoke-exposed mice and air-exposed controls (indicated by arrows in the associated image). Further investigation revealed defective lipid handling in the vapor-exposed mice, suggesting that e-cigarette vapor disrupts AM functions at the lung’s air-liquid interface. Vapor exposure also blunted antiviral immunity and increased susceptibility to damaging lung inflammation during viral infection. Aran Singanayagam and Robert Snelgrove discuss the implications of e-cigarettes’ effect on innate immunity in the lung in the accompanying Commentary.

Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotineMatthew C. Madison, Cameron T. Landers, Bon-Hee Gu, Cheng-Yen Chang, Hui-Ying Tung, Ran You, Monica J. Hong, Nima Baghaei, Li-Zhen Song, Paul Porter, Nagireddy Putluri, Ramiro Salas, Brian E. Gilbert, Ilya Levental, Matthew J. Campen, David B. Corry, and Farrah Kheradmand (ASCI) http://jci.me/128531

Less burn, more fat: electronic cigarettes and pulmonary lipid homeostasisAran Singanayagam and Robert J. Snelgrove http://jci.me/131336

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JCI | Features

JCI Review Series

Mechanisms Underlying the Metabolic SyndromeSeries Editor: Philipp E. Scherer

Biological and clinical insights into the metabolic syndrome

Obesity often occurs with a quintessential array of metabolic abnormalities: elevations in blood pressure, visceral fat, and circulating blood lipids and, importantly, insulin resistance. Together, this constellation of conditions constitutes the metabolic syndrome and forecasts an individual’s increased risk of developing cardiovascular diseases and type 2 diabetes. Although the metabolic syndrome presents as dysfunction across multiple tissues, its onset stems from pathological increases in adipose tissue. In this issue, nine reviews conceptualized by series editor Philipp Scherer delve into the complex biology underlying the metabolic syndrome. These reviews address adipocyte and β cell dysfunction in the metabolic syndrome; the functions of adipose tissue fibrosis, the microbiome, and exosomal communication in obesity; and the concepts we use to define metabolic health. The accompanying figure from Lavanya Vishvanath and Rana Gupta’s Review compares the distribution of fat in lipodystrophy, pathologic obesity, and metabolically healthy obesity.

Metabolically healthy obesity: facts and fantasiesGordon I. Smith, Bettina Mittendorfer, and Samuel Klein (ASCI) http://jci.me/129186

Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndromeC. Ronald Kahn (ASCI), Guoxiao Wang, and Kevin Y. Lee http://jci.me/129187

β Cell dysfunction during progression of metabolic syndrome to type 2 diabetesLaura I. Hudish, Jane E.B. Reusch, and Lori Sussel http://jci.me/129188

What lipodystrophies teach us about the metabolic syndromeJake P. Mann and David B. Savage http://jci.me/129190

Contribution of adipogenesis to healthy adipose tissue expansion in obesityLavanya Vishvanath and Rana K. Gupta http://jci.me/129191

Deciphering the cellular interplays underlying obesity-induced adipose tissue fibrosisGeneviève Marcelin, Ana Letícia M. Silveira, Laís Bhering Martins, Adaliene V.M. Ferreira, and Karine Clément http://jci.me/129192

Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndromeShunbun Kita, Norikazu Maeda, and Iichiro Shimomura http://jci.me/129193

The gut microbiome and metabolic syndromeKruttika Dabke, Gustaf Hendrick, and Suzanne Devkota http://jci.me/129194

CNS-targeting pharmacological interventions for the metabolic syndromeKerstin Stemmer, Timo D. Müller, Richard D. DiMarchi, Paul T. Pfluger, and Matthias H. Tschöp http://jci.me/129195

j c i . o r g / t h i s - m o n t h o c t o b e r 2 0 1 9 7

Current research articles

clinical medicineIdentifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade–refractory idiopathic multicentric Castleman disease p. 4David C. Fajgenbaum, Ruth-Anne Langan, Alberto Sada Japp, Helen L. Partridge, Sheila K. Pierson, Amrit Singh, Daniel J. Arenas, Jason R. Ruth, Christopher S. Nabel, Katie Stone, Mariko Okumura, Anthony Schwarer, Fábio Freire Jose, Nelson Hamerschlak, Gerald B. Wertheim, Michael B. Jordan, Adam D. Cohen, Vera Krymskaya, Arthur Rubenstein, Michael R. Betts, Taku Kambayashi, Frits van Rhee, and Thomas S. Uldrick http://jci.me/126091

Genetic hallmarks of recurrent/metastatic adenoid cystic carcinomaAllen S. Ho, Angelica Ochoa, Gowtham Jayakumaran, Ahmet Zehir, Cristina Valero Mayor, Justin Tepe, Vladimir Makarov, Martin G. Dalin, Jie He, Mark Bailey, Meagan Montesion, Jeffrey S. Ross, Vincent A. Miller, Lindsay Chan, Ian Ganly, Snjezana Dogan, Nora Katabi, Petros Tsipouras, Patrick Ha, Nishant Agrawal, David B. Solit, P. Andrew Futreal, Adel K. El Naggar, Jorge S. Reis-Filho, Britta Weigelt, Alan L. Ho, Nikolaus Schultz, Timothy A. Chan, and Luc G.T. Morris http://jci.me/128227

The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis p. 4Karthik Suresh, Jarushka Naidoo, Qiong Zhong, Ye Xiong, Jennifer Mammen, Marcia Villegas de Flores, Laura Cappelli, Aanika Balaji, Tsvi Palmer, Patrick M. Forde, Valsamo Anagnostou, David S. Ettinger, Kristen A. Marrone, Ronan J. Kelly, Christine L. Hann, Benjamin Levy, Josephine L. Feliciano, Cheng-Ting Lin, David Feller-Kopman, Andrew D. Lerner, Hans Lee, Majid Shafiq, Lonny Yarmus, Evan J. Lipson, Mark Soloski, Julie R. Brahmer, Sonye K. Danoff, and Franco D’Alessio http://jci.me/128654

endocrinologymTORC1-to-AMPK switching underlies β cell metabolic plasticity during maturation and diabetesRami Jaafar, Stella Tran, Ajit N. Shah, Gao Sun, Martin Valdearcos, Piero Marchetti, Matilde Masini, Avital Swisa, Simone Giacometti, Ernesto Bernal-Mizrachi, Aleksey Matveyenko, Matthias Hebrok, Yuval Dor, Guy A. Rutter, Suneil K. Koliwad (ASCI), and Anil Bhushan http://jci.me/127021

PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanismsPeng Zhou, Anna Santoro, Odile D. Peroni, Andrew T. Nelson, Alan Saghatelian, Dionicio Siegel, and Barbara B. Kahn (ASCI) http://jci.me/127092

Gene loci associated with insulin secretion in islets from nondiabetic mice p. 3Mark P. Keller, Mary E. Rabaglia, Kathryn L. Schueler, Donnie S. Stapleton, Daniel M. Gatti, Matthew Vincent, Kelly A. Mitok, Ziyue Wang, Takanao Ishimura, Shane P. Simonett, Christopher H. Emfinger, Rahul Das, Tim Beck, Christina Kendziorski, Karl W. Broman, Brian S. Yandell, Gary A. Churchill, and Alan D. Attie http://jci.me/129143

geneticsPolymerase δ deficiency causes syndromic immunodeficiency with replicative stressCecilia Domínguez Conde, Özlem Yüce Petronczki, Safa Baris, Katharina L. Willmann, Enrico Girardi, Elisabeth Salzer, Stefan Weitzer, Rico Chandra Ardy, Ana Krolo, Hanna Ijspeert, Ayca Kiykim, Elif Karakoc-Aydiner, Elisabeth Förster-Waldl, Leo Kager, Winfried F. Pickl, Giulio Superti-Furga, Javier Martínez, Joanna I. Loizou, Ahmet Ozen, Mirjam van der Burg, and Kaan Boztug http://jci.me/128903

Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome developmentPu Wang, Feng Yan, Zhijun Li, Yanbao Yu, Scott E. Parnell, and Yue Xiong http://jci.me/129107

hepatologyNeutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223Carolina Jimenez Calvente, Masahiko Tameda, Casey D. Johnson, Hana del Pilar, Yun Chin Lin, Nektaria Adronikou, Xavier De Mollerat Du Jeu, Cristina Llorente, Josh Boyer, and Ariel E. Feldstein (ASCI) http://jci.me/122258

Degradation of splicing factor SRSF3 contributes to progressive liver diseaseDeepak Kumar, Manasi Das, Consuelo Sauceda, Lesley G. Ellies, Karina Kuo, Purva Parwal, Mehak Kaur, Lily Jih, Gautam K. Bandyopadhyay, Douglas Burton, Rohit Loomba, Olivia Osborn, and Nicholas J.G. Webster http://jci.me/127374

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Current research articles

immunologyA distinct subset of FcγRI-expressing Th1 cells exert antibody-mediated cytotoxic activityDiana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Yariv Wine, Corey Saperia, Lior Tal, Haim Gutman, Alexander Tsivian, Ronen Brenner, Eiman Abu Bandora, Nathan E. Reticker-Flynn, Peleg Rider, and Yaron Carmi http://jci.me/127590

Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophagesDavid P. De Souza, Adrian Achuthan, Man K.S. Lee, Katrina J. Binger, Ming-Chin Lee, Sophia Davidson, Dedreia L. Tull, Malcolm J. McConville, Andrew D. Cook, Andrew J. Murphy, John A. Hamilton, and Andrew J. Fleetwood http://jci.me/127597

Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice p. 2Yufeng Liu, Michela Perego, Qiang Xiao, Yumei He, Shuyu Fu, Juan He, Wangkai Liu, Xing Li, Yanlai Tang, Xiaoyu Li, Weiming Yuan, Wei Zhou, Fan Wu, Chunhong Jia, Qiliang Cui, George S. Worthen, Erik A. Jensen, Dmitry I. Gabrilovich, and Jie Zhou http://jci.me/128164

Innate and adaptive nasal mucosal immune responses following experimental human pneumococcal colonizationSimon P. Jochems, Karin de Ruiter, Carla Solórzano, Astrid Voskamp, Elena Mitsi, Elissavet Nikolaou, Beatriz F. Carniel, Sherin Pojar, Esther L. German, Jesús Reiné, Alessandra Soares-Schanoski, Helen Hill, Rachel Robinson, Angela D. Hyder-Wright, Caroline M. Weight, Pascal F. Durrenberger, Robert S. Heyderman, Stephen B. Gordon, Hermelijn H. Smits, Britta C. Urban, Jamie Rylance, Andrea M. Collins, Mark D. Wilkie, Lepa Lazarova, Samuel C. Leong, Maria Yazdanbakhsh, and Daniela M. Ferreira http://jci.me/128865

metabolismIncreased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes p. 2Jenny E. Kanter, Baohai Shao, Farah Kramer, Shelley Barnhart, Masami Shimizu-Albergine, Tomas Vaisar, Mark J. Graham, Rosanne M. Crooke, Clarence R. Manuel, Rebecca A. Haeusler, Daniel Mar, Karol Bomsztyk, John E. Hokanson, Gregory L. Kinney, Janet K. Snell-Bergeon, Jay W. Heinecke, and Karin E. Bornfeldt http://jci.me/127308

nephrologyCrystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney diseaseJacob A. Torres, Mina Rezaei, Caroline Broderick, Louis Lin, Xiaofang Wang, Bernd Hoppe, Benjamin D. Cowley Jr., Vincenzo Savica, Vicente E. Torres, Saeed Khan, Ross P. Holmes, Michal Mrug, and Thomas Weimbs http://jci.me/128503

neurosciencePotential role of iron in repair of inflammatory demyelinating lesionsNathanael J. Lee, Seung-Kwon Ha, Pascal Sati, Martina Absinta, Govind Nair, Nicholas J. Luciano, Emily C. Leibovitch, Cecil C. Yen, Tracey A. Rouault, Afonso C. Silva, Steven Jacobson, and Daniel S. Reich (ASCI) http://jci.me/126809

Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsyJang Keun Kim, Jun Cho, Se Hoon Kim, Hoon-Chul Kang, Dong-Seok Kim, V. Narry Kim, and Jeong Ho Lee http://jci.me/127032

Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injuryDylan Laug, Teng-Wei Huang, Navish A. Bosquez Huerta, Anna Yu-Szu Huang, Debosmita Sardar, Joshua Ortiz-Guzman, Jeffrey C. Carlson, Benjamin R. Arenkiel, Chay T. Kuo, Carrie A. Mohila, Stacey M. Glasgow, Hyun Kyoung Lee, and Benjamin Deneen http://jci.me/127492

Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databasesRong Cai, Yu Zhang, Jacob E. Simmering, Jordan L. Schultz, Yuhong Li, Irene Fernandez-Carasa, Antonella Consiglio, Angel Raya, Philip M. Polgreen, Nandakumar S. Narayanan, Yanpeng Yuan, Zhiguo Chen, Wenting Su, Yanping Han, Chunyue Zhao, Lifang Gao, Xunming Ji, Michael J. Welsh (ASCI), and Lei Liu http://jci.me/129987

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oncologyHsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradationChaoyun Pan, Jaemoo Chun, Dan Li, Austin C. Boese, Jie Li, JiHoon Kang, Anna Umano, Yunhan Jiang, Lina Song, Kelly R. Magliocca, Zhuo G. Chen, Nabil F. Saba, Dong M. Shin, Taofeek K. Owonikoko, Sagar Lonial, Lingtao Jin, and Sumin Kang http://jci.me/125963

Immune overdrive signature in colorectal tumor subset predicts poor clinical outcomeMarwan Fakih, Ching Ouyang, Chongkai Wang, Travis Yiwey Tu, Maricel C. Gozo, May Cho, Marvin Sy, Jeffrey A. Longmate, and Peter P. Lee (ASCI) http://jci.me/127046

Type I IFN protects cancer cells from CD8+ T cell–mediated cytotoxicity after radiationJianzhou Chen, Yunhong Cao, Bostjan Markelc, Jakob Kaeppler, Jenny A.F. Vermeer, and Ruth J. Muschel http://jci.me/127458

Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damagePayel Chatterjee, Michael T. Schweizer, Jared M. Lucas, Ilsa Coleman, Michael D. Nyquist, Sander B. Frank, Robin Tharakan, Elahe Mostaghel, Jun Luo, Colin C. Pritchard, Hung-Ming Lam, Eva Corey, Emmanuel S. Antonarakis, Samuel R. Denmeade, and Peter S. Nelson http://jci.me/127613

Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcomaIan Bayles, Malgorzata Krajewska, W. Dean Pontius, Alina Saiakhova, James J. Morrow, Cynthia Bartels, Jim Lu, Zachary J. Faber, Yuriy Fedorov, Ellen S. Hong, Jaret M. Karnuta, Brian Rubin, Drew J. Adams, Rani E. George, and Peter C. Scacheri http://jci.me/127718

Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancerMark P. Labrecque, Ilsa M. Coleman, Lisha G. Brown, Lawrence D. True, Lori Kollath, Bryce Lakely, Holly M. Nguyen, Yu C. Yang, Rui M. Gil da Costa, Arja Kaipainen, Roger Coleman, Celestia S. Higano, Evan Y. Yu, Heather H. Cheng, Elahe A. Mostaghel, Bruce Montgomery, Michael T. Schweizer, Andrew C. Hsieh, Daniel W. Lin, Eva Corey, Peter S. Nelson, and Colm Morrissey http://jci.me/128212

Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacyYan-ping Xu, Lei Lv, Ying Liu, Matthew D. Smith, Wen-Cai Li, Xian-ming Tan, Meng Cheng, Zhijun Li, Michael Bovino, Jeffrey Aubé, and Yue Xiong http://jci.me/129317

pulmonologyIL-1β dominates the promucin secretory cytokine profile in cystic fibrosis p. 5Gang Chen, Ling Sun, Takafumi Kato, Kenichi Okuda, Mary B. Martino, Aiman Abzhanova, Jennifer M. Lin, Rodney C. Gilmore, Bethany D. Batson, Yvonne K. O’Neal, Allison S. Volmer, Hong Dang, Yangmei Deng, Scott H. Randell, Brian Button, Alessandra Livraghi-Butrico, Mehmet Kesimer, Carla M.P. Ribeiro, Wanda K. O’Neal, and Richard C. Boucher (ASCI) http://jci.me/125669

Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine p. 5Matthew C. Madison, Cameron T. Landers, Bon-Hee Gu, Cheng-Yen Chang, Hui-Ying Tung, Ran You, Monica J. Hong, Nima Baghaei, Li-Zhen Song, Paul Porter, Nagireddy Putluri, Ramiro Salas, Brian E. Gilbert, Ilya Levental, Matthew J. Campen, David B. Corry, and Farrah Kheradmand (ASCI) http://jci.me/128531

vascular biologyLysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4Daisuke Yasuda, Daiki Kobayashi, Noriyuki Akahoshi, Takayo Ohto-Nakanishi, Kazuaki Yoshioka, Yoh Takuwa, Seiya Mizuno, Satoru Takahashi, and Satoshi Ishii http://jci.me/121955

STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockadeHannah Yang, Won Suk Lee, So Jung Kong, Chang Gon Kim, Joo Hoon Kim, Sei Kyung Chang, Sewha Kim, Gwangil Kim, Hong Jae Chon, and Chan Kim http://jci.me/125413

Dengue virus–elicited tryptase induces endothelial permeability and shock p. 3Abhay P.S. Rathore, Chinmay Kumar Mantri, Siti A.B. Aman, Ayesa Syenina, Justin Ooi, Cyril J. Jagaraj, Chi Ching Goh, Hasitha Tissera, Annelies Wilder-Smith, Lai Guan Ng, Duane J. Gubler, and Ashley L. St. John http://jci.me/128426

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Circulating apolipoprotein E influences bone repair 11

A mouse model of progressive metabolic liver disease 12

Syndecan-1 promotes pulmonary fibrosis 13

Model identifies HIV-1 reservoir susceptibility to bNAbs 13

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

October 2019

Gene therapy–mediated restoration in hyperargininemia p. 10

This Month

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Christopher M. Adams

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Zoltan Arany

Hossein Ardehali

Kenneth I. Ataga

Joseph Bass

Alexander G. Bassuk

Antonio C. Bianco

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

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Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

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Timothy Chan

Yuan Chang

Zhou-Feng Chen

Keith A. Choate

Wendy Chung

Craig M. Coopersmith

George Cotsarelis

Peter Crawford

Lisa L. Cunningham

Ronald P. DeMatteo

Elia J. Duh

Sarah K. England

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Lawrence Fong

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Anthony R. French

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Noyan Gokce

Raphaela Goldbach-Mansky

Daniel R. Goldstein

Douglas K. Graham

Khalid A. Hanafy

Eric B. Haura

John Cijiang He

Robert O. Heuckeroth

Cory M. Hogaboam

Young-Kwon Hong

Benjamin D. Humphreys

Ken Inoki

Shingo Kajimura

Pawel Kalinski

John Y. Kao

Michael G. Kaplitt

Thomas W.H. Kay

Barbara I. Kazmierczak

Hans-Peter Kiem

William Y. Kim

David G. Kirsch

Claire E. Lewis

Mathias Lichterfeld

André Lieber

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Ivan Maillard

Ziad Mallat

Peter Mannon

Franck Mauvais-Jarvis

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

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Joshua D. Milner

Satdarshan (Paul) Singh Monga

Hidayatullah G. Munshi

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Fayyaz S. Sutterwala

Shu Takeda

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AAV-mediated hepatic arginase-1 restoration improves hyperargininemia-associated leukodystrophy

Hyperargininemia results from hepatic arginase deficiency and is characterized by onset of spastic diplegia, clonus, and/or hyperreflexia in early childhood and later progresses to loss of activity, seizures, growth retar-dation, intellectual disability, and neurological decline. The disease is rare, and the drivers of disease etiology are poorly understood. In this issue, Xiao-

Bo Liu and colleagues used an arginase-1–deficient mouse model to evaluate the neurological changes and underlying genetic alterations associated with hyper-argininemia. Dysmyelination occurred within the first two weeks after birth, with associated oligodendrocyte impairment. Restoration of hepatic arginase-1 via adeno-associated virus–mediated (AAV-mediated) gene delivery increased myelinated axon density and integrity to near-normal amounts. Together, these results indicate that hepatic arginase deficiency promotes leukodystrophy in the brain and spinal cord, sparing the peripheral nervous system, and support further evaluation of AAV-mediated hepatic gene therapy for treating this rare and dev-astating disease. The cover image shows restoration of basal dendritic arbors of layer V pyramidal tract neurons in an AAV-treated arginase-1–deficient mouse.

Hepatic arginase deficiency fosters dysmyelination during postnatal CNS developmentXiao-Bo Liu, Jillian R. Haney, Gloria Cantero, Jenna R. Lambert, Marcos Otero-Garcia, Brian Truong, Andrea Gropman, Inma Cobos, Stephen D. Cederbaum, and Gerald S. Lipshutz http://jci.me/130260

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Editor’s picks

on the jci insight cover

Age-associated increases in apolipoprotein E linked to dysfunctional bone repairElderly individuals are at increased risk of serious complications after bone fracture; however, the factors that lead to age-associated dysfunctional bone repair are poorly understood. Rong Huang and colleagues used a variety of methods, including parabiosis, genetic KO, and siRNA-mediated knockdown, to identify a role for circulating apolipoprotein E (ApoE) in impaired bone repair. ApoE was shown to increase in both mice and humans with age and to inhibit bone fracture healing and osteoblast differentiation. In murine models, a reduction of ApoE increased bone deposition (see the accompanying image) and mechanical strength at the site of fracture, while recombinant ApoE depressed differentiation and altered metabolism in purified osteoblasts. Together, these results identify circulating ApoE as an age-associated factor that directly impairs bone healing and having potential as a therapeutic target to promote bone repair.

Lowering circulating apolipoprotein E levels improves aged bone fracture healingRong Huang, Xiaohua Zong, Puviindran Nadesan, Janet L. Huebner, Virginia B. Kraus, James P. White, Phillip J. White, and Gurpreet S. Baht http://jci.me/129144

Dietary fat and sucrose promote cardiac fibrosis

bone biology

aging

Calorie restriction (CR) variably affects age-associated dysfunction in nonhuman primates (NHPs) and humans. Two indepen-dent studies at the University of Wisconsin–Madison (UW) and the National Institute on Aging (NIA) examined CR in NHPs. However, only the UW study observed an increase in longevity of the CR cohort, compared with controls. Niranjana Natarajan, Ana Vujic, and colleagues have now examined left ventricle tissue samples from NHPs in these studies and observed elevated cardiac fibrosis in control and CR animals in the UW study compared with

animals in the NIA study. A key difference between the NIA and UW studies was the diet administered, with higher fat and sucrose content in the UW diet. Evaluation of similar diets in a mouse model revealed an increase in cardiac fibrosis in response to diets with increased sucrose and fat content (UW diet and a modified NIA diet). Furthermore, transcrip-tomic profiling showed that long-term administration of UW and modified NIA diets was linked to diet-induced activation of myocardial oxidative phosphorylation and cardiac muscle contraction pathways.

Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeysNiranjana Natarajan, Ana Vujic, Jishnu Das, Annie C. Wang, Krystal K. Phu, Spencer H. Kiehm, Elisabeth M. Ricci-Blair, Anthony Y. Zhu, Kelli L. Vaughan, Ricki J. Colman, Julie A. Mattison, and Richard T. Lee (ASCI) http://jci.me/128685

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JCI Insight | Editor’s picks

12

Growth hormone signaling in adipocytes underlies fatty liver disease progression

hepatology

inflammation

Steroid-refractory acute GVHD characterized by T cell–independent signatureGastrointestinal acute graft-versus-host disease (aGVHD) is a common and often severe complication of allogeneic hematopoietic cell transplanta-tion. Primary aGVHD treatment is high-dose corticosteroids, although only approximately one-half of patients fully recover. Most patients with steroid-refractory gastrointestinal aGVHD die within weeks due to disease complications. Shernan Holtan, Ashraf Shabaneh, and colleagues evaluated gene expression profiles in intestinal biopsies from patients with aGVHD both at onset and when diagnosed with steroid-refractory aGVHD, and compared these profiles with healthy intestinal biopsies. At aGVHD diagnosis, expression of several immune tolerance–associated genes was high, but it decreased in the steroid-refractory state. Steroid-refractory aGVHD was also associated with increased metallothionein and M2 macrophage gene expression, but there was no change in T cells, which are often targeted to treat steroid-refractory aGVHD. Many microbial genes were

reduced in patients with shortened survival compared with those with prolonged survival. Finally, steroid-refractory patients with a favorable prognosis exhibited a distinct gene signature, suggesting activation of Smoothened. These results identify several potential areas for therapeutic exploration in life-threatening aGVHD.

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host diseaseShernan G. Holtan, Ashraf Shabaneh, Brian C. Betts, Armin Rashidi, Margaret L. MacMillan, Celalletin Ustun, Khalid Amin, Byron P. Vaughn, Justin Howard, Alexander Khoruts, Mukta Arora, Todd E. DeFor, Darrell Johnson, Bruce R. Blazar, Daniel J. Weisdorf, and Jinhua Wang http://jci.me/129762

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) incidence has risen along with rates of metabolic syndromes. These diseases can progress to hepatocellular carcinoma (HCC) and often are only treatable by liver transplantation. Current animal models do not fully capture the human disease spectrum; therefore, identification of potential therapies has been challenging. As growth hormone (GH) signaling deficiency has been linked to NAFLD and NASH, Kevin Corbit and colleagues developed and

evaluated a murine model lacking the GH signal transducer JAK2 in hepatocytes. These mice (JAK2L mice) spontaneously developed phenotypes observed in patients, beginning with metabolic syndrome and progressing to NAFLD, NASH, and HCC in some cases. Adipocyte-specific JAK2 deletion in JAK2L mice (JAK2LA mice) prevented disease progression (see the accompanying image), implicating GH signaling in adipocytes as a driver of disease. Collectively, these results provide a murine model of progressive fatty liver disease that

recapitulates human etiology and support GH signaling in adipocytes as a therapeutic target.

Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinomaKevin C. Corbit, Camella G. Wilson, Dylan Lowe, Jennifer L. Tran, Nicholas B. Vera, Michelle Clasquin, Aras N. Mattis, and Ethan J. Weiss http://jci.me/131310

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JCI Insight | Editor’s picks

aids/hiv

Syndecan-1–dependent regulation of extracellular vesicle cargo promotes lung fibrosisIdiopathic pulmonary fibrosis (IPF) is a chronic and often fatal lung disease of heterogenous origins. Recent studies have implicated alteration in the alveolar lung epithelium in lung fibrosis etiology; however, the mechanisms by which maladaptive pulmonary epithelium promote fibrosis are poorly understood. Tanyalak Parimon and colleagues determined that syndecan-1 is overexpressed in lung epithelium of IPF patients and mice exposed to bleomycin injury. Syndecan-1 was shown to promote fibrotic pathways, including TGF-β and Wnt, in alveolar type II epithelial cells. In addition, syndecan-1 regulated the packaging of microRNA cargo into extracellular vesicles (EVs), including microRNAs that influence fibrosis and epithelial plasticity. In particular, EVs from the lungs of syndecan-1–deficient bleomycin-treated mice had antifibrotic effects when given to WT mice following bleomycin injury. Together, these results support syndecan-1 as a profibrotic factor in lung disease.

Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesiclesTanyalak Parimon, Changfu Yao, David M. Habiel, Lingyin Ge, Stephanie A. Bora, Rena Brauer, Christopher M. Evans, Ting Xie, Felix Alonso-Valenteen, Lali K. Medina-Kauwe, Dianhua Jiang, Paul W. Noble, Cory M. Hogaboam, Nan Deng, Olivier Burgy, Travis J. Antes, Melanie Königshoff, Barry R. Stripp, Sina A. Gharib, and Peter Chen http://jci.me/129359

Model predicts broadly neutralizing antibody resistance in individual HIV-1 reservoirsDue to their potency and ability to protect against multiple HIV-1 strains, broadly neutralizing antibodies (bNAbs) are an attractive target for eradication and prevention of HIV-1 infections. The viral reservoir in HIV-infected individuals is highly heterogenous, with potential to harbor bNAb- resistant strains that could prevent disease control. Wen-Han Yu and colleagues developed a Bayesian machine learning–based model to predict effective bNAb combinations based on HIV-1 envelope (Env) sequence and predicted glycan occupancy. The authors applied the model to PBMC-derived Env sequences from HIV-1–infected patients to determine the presence of neutraliza-tion resistance in individual reservoirs and were able to identify the bNAb combinations that theoretically provided full neutralization. Moreover, levels of predicted viral reservoir susceptibility were consistent with neutralization signatures of rebound viruses in individuals undergoing antiretroviral treatment interruption. This model’s predictive capacity has potential to facilitate clinical use of bNAbs.

Predicting the broadly neutralizing antibody susceptibility of the HIV reservoirWen-Han Yu, David Su, Julia Torabi, Christine M. Fennessey, Andrea Shiakolas, Rebecca Lynch, Tae-Wook Chun, Nicole Doria-Rose, Galit Alter, Michael S. Seaman, Brandon F. Keele, Douglas A. Lauffenburger, and Boris Julg http://jci.me/130153

Immunologypulmonology

Characterization of tumor-infiltrating B cells in breast cancerInfiltration of immune cell populations, particularly T cell subsets, has been linked to cancer outcome for a variety of tumors. Recently, B cells have been identified as part of the tumor-infiltrating lymphocyte (TIL) population in breast cancer; however, it is not clear how these TIL-B cells affect overall tumor immune response. Soizic Garaud, Laurence Buisseret, and colleagues analyzed TIL-B cell density in triple-negative and HER2+ breast cancer and confirmed a correlation between TIL-B cell density and improved prognosis. TIL-B cells were found at higher densities in tumors compared with normal breast tissues and were associated with an increase in other TILs, tumor grade, proliferation, and hormone receptor negativity. Germinal center TIL-B cells were present in tumors with a high level of immune infiltrate and were present in tertiary lymphoid structures. Moreover, TIL-B cells were activated in response to B cell receptor stimulation, indicating that these cells are part of an active humoral response that promotes antitumor immunity.

Tumor-infiltrating B cells signal functional humoral immune responses in breast cancerSoizic Garaud, Laurence Buisseret, Cinzia Solinas, Chunyan Gu-Trantien, Alexandre de Wind, Gert Van den Eynden, Celine Naveaux, Jean-Nicolas Lodewyckx, Anaïs Boisson, Hughes Duvillier, Ligia Craciun, Lieveke Ameye, Isabelle Veys, Marianne Paesmans, Denis Larsimont, Martine Piccart-Gebhart, and Karen Willard-Gallo http://jci.me/129641

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Current articlesTargeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapyMarco A. De Velasco, Yurie Kura, Kazuko Sakai, Yuji Hatanaka, Barry R. Davies, Hayley Campbell, Stephanie Klein, Youngsoo Kim, A. Robert MacLeod, Koichi Sugimoto, Kazuhiro Yoshikawa, Kazuto Nishio, and Hirotsugu Uemura http://jci.me/122688

A G protein–coupled, IP3/protein kinase C pathway controlling the synthesis of phosphaturic hormone FGF23Qing He, Lauren T. Shumate, Julia Matthias, Cumhur Aydin, Marc N. Wein, Jordan M. Spatz, Regina Goetz, Moosa Mohammadi, Antonius Plagge, Paola Divieti Pajevic, and Murat Bastepe (ASCI) http://jci.me/125007

Fibroblast-specific deletion of IL-1 receptor-1 reduces adverse cardiac remodeling following myocardial infarctionSumia A. Bageghni, Karen E. Hemmings, Nadira Y. Yuldasheva, Azhar Maqbool, Filomena O. Gamboa-Esteves, Neil E. Humphreys, Maj Simonsen Jackson, Christopher P. Denton, Sheila Francis, Karen E. Porter, Justin F.X. Ainscough, Emmanuel Pinteaux, Mark J. Drinkhill, and Neil A. Turner http://jci.me/125074

Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertilityZhiqiang Wang, Mingxiao Feng, Olubusayo Awe, Yaping Ma, Mingjie Shen, Ping Xue, Rexford Ahima, Andrew Wolfe, James Segars, and Sheng Wu http://jci.me/127817

Virus-induced cochlear inflammation in newborn mice alters auditory functionCathy Yea Won Sung, Maria C. Seleme, Shelby Payne, Stipan Jonjic, Keiko Hirose, and William Britt http://jci.me/128878

Cardiomyocyte d-dopachrome tautomerase protects against heart failureYina Ma, Kevin N. Su, Daniel Pfau, Veena S. Rao, Xiaohong Wu, Xiaoyue Hu, Lin Leng, Xin Du, Marta Piecychna, Kenneth Bedi, Stuart G. Campbell, Anne Eichmann, Jeffrey M. Testani, Kenneth B. Margulies, Richard Bucala, and Lawrence H. Young http://jci.me/128900

Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles p. 13Tanyalak Parimon, Changfu Yao, David M. Habiel, Lingyin Ge, Stephanie A. Bora, Rena Brauer, Christopher M. Evans, Ting Xie, Felix Alonso-Valenteen, Lali K. Medina-Kauwe, Dianhua Jiang, Paul W. Noble, Cory M. Hogaboam, Nan Deng, Olivier Burgy, Travis J. Antes, Melanie Königshoff, Barry R. Stripp, Sina A. Gharib, and Peter Chen http://jci.me/129359

Dual PPARα/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunctionCharikleia Kalliora, Ioannis D. Kyriazis, Shin-ichi Oka, Melissa J. Lieu, Yujia Yue, Estela Area-Gomez, Christine J. Pol, Ying Tian, Wataru Mizushima, Adave Chin, Diego Scerbo, P. Christian Schulze, Mete Civelek, Junichi Sadoshima, Muniswamy Madesh, Ira J. Goldberg, and Konstantinos Drosatos http://jci.me/129556

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease p. 12Shernan G. Holtan, Ashraf Shabaneh, Brian C. Betts, Armin Rashidi, Margaret L. MacMillan, Celalletin Ustun, Khalid Amin, Byron P. Vaughn, Justin Howard, Alexander Khoruts, Mukta Arora, Todd E. DeFor, Darrell Johnson, Bruce R. Blazar, Daniel J. Weisdorf, and Jinhua Wang http://jci.me/129762

Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cellsAnfei Huang, Prashant V. Shinde, Jun Huang, Tina Senff, Haifeng C. Xu, Cassandra Margotta, Dieter Häussinger, Thomas E. Willnow, Jinping Zhang, Aleksandra A. Pandyra, Jörg Timm, Sascha Weggen, Karl S. Lang, and Philipp A. Lang http://jci.me/129856

Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration programStefanie Geisler, Ryan A. Doan, Galen C. Cheng, Aysel Cetinkaya-Fisgin, Shay X. Huang, Ahmet Höke, Jeffrey Milbrandt, and Aaron DiAntonio http://jci.me/129920

Predicting the broadly neutralizing antibody susceptibility of the HIV reservoir p. 13Wen-Han Yu, David Su, Julia Torabi, Christine M. Fennessey, Andrea Shiakolas, Rebecca Lynch, Tae-Wook Chun, Nicole Doria-Rose, Galit Alter, Michael S. Seaman, Brandon F. Keele, Douglas A. Lauffenburger, and Boris Julg http://jci.me/130153

Comparison of CAR-T19 and autologous stem cell transplantation for refractory/relapsed non-Hodgkin’s lymphomaCaixia Li, Ying Zhang, Changfeng Zhang, Jia Chen, Xiaoyan Lou, Xiaochen Chen, Liqing Kang, Nan Xu, Minghao Li, Jingwen Tan, Xiuli Sun, Jin Zhou, Zhen Yang, Xiangping Zong, Pu Wang, Ting Xu, Changju Qu, Haiwen Huang, Zhengming Jin, Lei Yu, and Depei Wu http://jci.me/130195

Hepatic arginase deficiency fosters dysmyelination during postnatal CNS development p. 10Xiao-Bo Liu, Jillian R. Haney, Gloria Cantero, Jenna R. Lambert, Marcos Otero-Garcia, Brian Truong, Andrea Gropman, Inma Cobos, Stephen D. Cederbaum, and Gerald S. Lipshutz http://jci.me/130260

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Current articles

In situ metabolomics of aldosterone-producing adenomasMasanori Murakami, Yara Rhayem, Thomas Kunzke, Na Sun, Annette Feuchtinger, Philippe Ludwig, Tim Matthias Strom, Celso Gomez-Sanchez, Thomas Knösel, Thomas Kirchner, Tracy Ann Williams, Martin Reincke, Axel Karl Walch, and Felix Beuschlein http://jci.me/130356

High-fat diet–induced vagal afferent dysfunction via upregulation of 2-pore domain potassium TRESK channelGintautas Grabauskas, Xiaoyin Wu, ShiYi Zhou, JiYao Li, Jun Gao, and Chung Owyang (ASCI) http://jci.me/130402

RNA processing genes characterize RNA splicing and further stratify lower-grade gliomaRui-Chao Chai, Yi-Ming Li, Ke-Nan Zhang, Yu-Zhou Chang, Yu-Qing Liu, Zheng Zhao, Zhi-Liang Wang, Yuan-Hao Chang, Guan-Zhang Li, Kuan-Yu Wang, Fan Wu, and Yong-Zhi Wang http://jci.me/130591

Suboptimal hydration remodels metabolism, promotes degenerative diseases, and shortens lifeMichele D. Allen, Danielle A. Springer, Maurice B. Burg, Manfred Boehm, and Natalia I. Dmitrieva http://jci.me/130949

Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma p. 12Kevin C. Corbit, Camella G. Wilson, Dylan Lowe, Jennifer L. Tran, Nicholas B. Vera, Michelle Clasquin, Aras N. Mattis, and Ethan J. Weiss http://jci.me/131310

mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humansVictor G. Puelles, James W. van der Wolde, Nicola Wanner, Markus W. Scheppach, Luise A. Cullen-McEwen, Tillmann Bork, Maja T. Lindenmeyer, Lukas Gernhold, Milagros N. Wong, Fabian Braun, Clemens D. Cohen, Michelle M. Kett, Christoph Kuppe, Rafael Kramann, Turgay Saritas, Claudia R. van Roeyen, Marcus J. Moeller, Leon Tribolet, Richard Rebello, Yu B.Y. Sun, Jinhua Li, Gerard Müller-Newen, Michael D. Hughson, Wendy E. Hoy, Fermin Person, Thorsten Wiech, Sharon D. Ricardo, Peter G. Kerr, Kate M. Denton, Luc Furic, Tobias B. Huber, David J. Nikolic-Paterson, and John F. Bertram http://jci.me/99271

Monocyte glycolysis determines CD8+ T cell functionality in human Chagas diseaseLiliana María Sanmarco, Natalia Eberhardt, Gastón Bergero, Luz Piedad Quebrada Palacio, Pamela Martino Adami, Laura Marina Visconti, Ángel Ramón Minguez, Yolanda Hernández-Vasquez, Eugenio Antonio Carrera Silva, Laura Morelli, Miriam Postan, and Maria Pilar Aoki http://jci.me/123490

iPSC-derived functional human neuromuscular junctions model the pathophysiology of neuromuscular diseasesChuang-Yu Lin, Michiko Yoshida, Li-Tzu Li, Akihiro Ikenaka, Shiori Oshima, Kazuhiro Nakagawa, Hidetoshi Sakurai, Eriko Matsui, Tatsutoshi Nakahata, and Megumu K. Saito http://jci.me/124299

PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune diseaseRyan Galea, Hendrik Nel, Meghna Talekar, Xiao Liu, Joshua D. Ooi, Megan Huynh, Sara Hadjigol, Kate J. Robson, Yi Tian Ting, Suzanne Cole, Karyn Cochlin, Shannon Hitchcock, Bijun Zeng, Suman Yekollu, Martine Boks, Natalie Goh, Helen Roberts, Jamie Rossjohn, Hugh H. Reid, Ben J. Boyd, Ravi Malaviya, David J. Shealy, Daniel G. Baker, Loui Madakamutil, A. Richard Kitching, Brendan J. O’Sullivan, and Ranjeny Thomas http://jci.me/126025

ROR1-CAR T cells are effective against lung and breast cancer in advanced microphysiologic 3D tumor modelsLars Wallstabe, Claudia Göttlich, Lena C. Nelke, Johanna Kühnemundt, Thomas Schwarz, Thomas Nerreter, Hermann Einsele, Heike Walles, Gudrun Dandekar, Sarah L. Nietzer, and Michael Hudecek http://jci.me/126345

Disruption of Robo2-Baiap2 integrated signaling drives cystic diseaseQinggang Li, Shaoyuan Cui, Qian Ma, Ying Liu, Hongyu Yu, GuangRui Geng, Ewud Agborbesong, Chongyu Ren, Kai Wei, Yingjie Zhang, Jurong Yang, Xueyuan Bai, Guangyan Cai, Yuansheng Xie, Xiaogang Li, and Xiangmei Chen http://jci.me/127602

Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1–dependent mechanismMalik Hamaidia, Hélène Gazon, Clotilde Hoyos, Gabriela Brunsting Hoffmann, Renaud Louis, Bernard Duysinx, and Luc Willems http://jci.me/128474

Inhibition of 4-aminobutyrate aminotransferase protects against injury-induced osteoarthritis in miceJie Shen, Cuicui Wang, Jun Ying, Taotao Xu, Audrey McAlinden, and Regis J. O’Keefe http://jci.me/128568

Dysregulated integrin αVβ3 and CD47 signaling promotes joint inflammation, cartilage breakdown, and progression of osteoarthritisQian Wang, Kazuhiro Onuma, Changhao Liu, Heidi Wong, Michelle S. Bloom, Eileen E. Elliott, Richard R.L. Cao, Nick Hu, Nithya Lingampalli, Orr Sharpe, Xiaoyan Zhao, Dong Hyun Sohn, Christin M. Lepus, Jeremy Sokolove, Rong Mao, Cecilia T. Cisar, Harini Raghu, Constance R. Chu, Nicholas J. Giori, Stephen B. Willingham, Susan S. Prohaska, Zhen Cheng, Irving L. Weissman, and William H. Robinson (ASCI) http://jci.me/128616

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Flip issue to read JCI content.

Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys p. 11Niranjana Natarajan, Ana Vujic, Jishnu Das, Annie C. Wang, Krystal K. Phu, Spencer H. Kiehm, Elisabeth M. Ricci-Blair, Anthony Y. Zhu, Kelli L. Vaughan, Ricki J. Colman, Julie A. Mattison, and Richard T. Lee (ASCI) http://jci.me/128685

Extracellular vesicles from endometriosis patients are characterized by a unique miRNA-lncRNA signatureKasra Khalaj, Jessica E. Miller, Harshavardhan Lingegowda, Asgerally T. Fazleabas, Steven L. Young, Bruce A. Lessey, Madhuri Koti, and Chandrakant Tayade http://jci.me/128846

Lowering circulating apolipoprotein E levels improves aged bone fracture healing p. 11Rong Huang, Xiaohua Zong, Puviindran Nadesan, Janet L. Huebner, Virginia B. Kraus, James P. White, Phillip J. White, and Gurpreet S. Baht http://jci.me/129144

Tumor-infiltrating B cells signal functional humoral immune responses in breast cancer p. 13Soizic Garaud, Laurence Buisseret, Cinzia Solinas, Chunyan Gu-Trantien, Alexandre de Wind, Gert Van den Eynden, Celine Naveaux, Jean-Nicolas Lodewyckx, Anaïs Boisson, Hughes Duvillier, Ligia Craciun, Lieveke Ameye, Isabelle Veys, Marianne Paesmans, Denis Larsimont, Martine Piccart-Gebhart, and Karen Willard-Gallo http://jci.me/129641

Stem cell transplantation impairs dendritic cell trafficking and herpesvirus immunityCarol A. Wilke, Mathew M. Chadwick, Paul R. Chan, Bethany B. Moore, and Xiaofeng Zhou http://jci.me/130210

Alteration of thyroid hormone signaling triggers the diabetes-induced pathological growth, remodeling, and dedifferentiation of podocytesValentina Benedetti, Angelo Michele Lavecchia, Monica Locatelli, Valerio Brizi, Daniela Corna, Marta Todeschini, Rubina Novelli, Ariela Benigni, Carlamaria Zoja, Giuseppe Remuzzi, and Christodoulos Xinaris http://jci.me/130249

Predictability of individual circadian phase during daily routine for medical applications of circadian clocksSandra Komarzynski, Matei Bolborea, Qi Huang, Bärbel Finkenstädt, and Francis Lévi http://jci.me/130423

Adoptive lymphocyte transfer to an HIV-infected progressor from an elite controllerStephen A. Migueles, Cheryl Chairez, Siying Lin, Noah V. Gavil, Danielle M. Rosenthal, Milad Pooran, Ven Natarajan, Adam Rupert, Robin Dewar, Tauseef Rehman, Brad T. Sherman, Joseph Adelsberger, Susan F. Leitman, David Stroncek, Caryn G. Morse, Mark Connors, H. Clifford Lane, and Joseph A. Kovacs (ASCI) http://jci.me/130664

Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brainGregory N. Ruegsegger, Patrick M. Vanderboom, Surendra Dasari, Katherine A. Klaus, Parijat Kabiraj, Christina B. McCarthy, Claudia F. Lucchinetti, and K. Sreekumaran Nair (ASCI) http://jci.me/130681

Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes after myocardial infarctionAlison K. Schroer, Matthew R. Bersi, Cynthia R. Clark, Qinkun Zhang, Lehanna H. Sanders, Antonis K. Hatzopoulos, Thomas L. Force, Susan M. Majka, Hind Lal, and W. David Merryman http://jci.me/131545

editorialA new editor and a new team for JCI InsightKathleen L. Collins (ASCI) http://jci.me/132119