jci.org/this-month

ALSO IN THIS ISSUE:

Complement activation complicates anti-VEGF therapy 2

Cardiac myofibroblasts clean up after myocardial infarction 4

TGF-β1 promotes recovery after acute brain injury 6

Blocking type I interferon boosts antiretroviral therapy 6

Review Series: Metabolism and inflammation edited by Alan R. Saltiel and Jerrold M. Olefsky 8

JCI Insight 12

A summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight

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January 2017 Metastatic vesicle trafficking in EMT p. 1

This Month

Christopher M. Adams

Maria-Luisa Alegre

Ravi K. Amaravadi

John K. Amory

Jennifer H. Anolik

Cristian Apetrei

Rajendra S. Apte

Zoltan Arany

Hossein Ardehali

Kenneth I. Ataga

Joseph Bass

Alexander G. Bassuk

Antonio C. Bianco

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

Sebastien G. Bouret

Jason Brenchley

Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

Stephen 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

Mark W. Feinberg

John H. Fingert

Robert Flaumenhaft

Edward A. Fon

Lawrence Fong

Nikolaos G. Frangogiannis

Anthony R. French

Terrence L. Geiger

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

Mariana J. Kaplan

Michael G. Kaplitt

Barbara I. Kazmierczak

Hans-Peter Kiem

William Y. Kim

David G. Kirsch

Mathias Lichterfeld

André Lieber

Michail S. Lionakis

Carey N. Lumeng

Leo Luznik

Ivan Maillard

Ziad Mallat

Peter Mannon

Franck Mauvais-Jarvis

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

Jason C. Mills

Joshua D. Milner

Satdarshan (Paul) Singh Monga

Hidayatullah G. Munshi

Matthias Nahrendorf

Mary Nakamura

Lisa F.P. Ng

Mark Nicolls

Laura J. Niedernhofer

Deborah V. Novack

S. Tiong Ong

Puneet Opal

Daniel Ory

Sophie Paczesny

Stephanie T. Page

Mary-Elizabeth Patti

Janos Peti-Peterdi

Fernando P. Polack

Matthew D. Ringel

Steven M. Rowe

Svati H. Shah

Vijay H. Shah

Alice T. Shaw

Rhonda F. Souza

Fayyaz S. Sutterwala

Shu Takeda

Natalie J. Torok

Stephen H. Tsang

Ellie Tzima

Mark C. Udey

Fumihiko Urano

Charles P. Venditti

Joseph M. Vinetz

Sing Sing Way

Bernd Wollnik

Minna Woo

Prescott G. Woodruff

Lori M. Zeltser

Yutong Zhao

Binhua P. Zhou

JCI Insight Consulting Editors

1j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 7

EditorHoward A. Rockman

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Associate EditorsSoman N. Abraham, Vann Bennett, Gerard C. Blobe, Kathleen M. Caron, Marc G. Caron, John P. Chute, Thomas M. Coffman, Anna Mae Diehl, Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Thomas Weber, Yiping Yang

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This MonthJanuary 2017

Metastatic vesicle trafficking during the epithelial-to-mesenchymal transition

On the JCI cover

The conversion of polarized epithelial cells into mesenchymal cells that migrate and invade the extracel-lular matrix, known as epithelial-to-mesenchymal transition (EMT), drives metastasis of epithelial cancers. During this shift, secretory vesicle trafficking is redirected toward the leading edge of the cell, promoting the formation of promigratory focal adhesions and cytoplasmic protrusions as well as the release of factors that drive extracellular matrix remodeling and angiogenesis. In this issue of the

JCI, a research team led by Jonathan Kurie uncovered a role for Golgi apparatus compaction in regulating vesicle trafficking during EMT. Golgi structural features were quantified during EMT in a metastatic lung adenocarcinoma model, and it was found that metastatic mesenchymal cells had enhanced Golgi organelle com-paction. Forced expression of ZEB1, which promotes EMT, also led to Golgi com-paction in multiple in vitro models. Transcriptional profiling of ZEB1-expressing cells suggested that the scaffolding protein PAQR11, which assembles multipro-tein complexes in the Golgi, was a key mediator of Golgi reorganization. Accord-ingly, increased expression of PAQR11 was associated with decreased survival in lung adenocarcinoma patients, and knockdown of PAQR11 impaired migration and invasion of lung adenocarcinoma cells. Together, these findings reveal an important role for PAQR11 in promoting cell motility, invasion, and metastasis during EMT. The accompanying image shows a normal bronchus within a human lung adenocarcinoma tissue section costained with DAPI (magenta) and antibod-ies against the Golgi protein GM130 (yellow) and collagen I (blue).

Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11Xiaochao Tan, Priyam Banerjee, Hou-Fu Guo, Stephen Ireland, Daniela Pankova, Young-ho Ahn, Irodotos Michail Nikolaidis, Xin Liu, Yanbin Zhao, Yongming Xue, Alan R. Burns, Jonathon Roybal, Don L. Gibbons, Tomasz Zal, Chad J. Creighton, Daniel Ungar, Yanzhuang Wang, and Jonathan M. Kurie http://jci.me/88736

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research

Editor’s picks

VEGF regulates deleterious complement activation in the retinaVEGF signaling maintains specialized vasculature that supports the functions of the outer retina, but elevated VEGF levels are linked to neovascularization and vision loss in patients with wet age-related macular degeneration (ARMD). Anti-VEGF therapies can be used to stabilize or improve vision, but some patients’ vision continues to deteriorate during treatment. Lindsay Keir and colleagues investigated whether anti-VEGF therapies perpetuate damage in nonresponsive patients by activating the complement system. There is evidence that genetic variation in complement factor H (CFH) contributes to poor response to anti-VEGF therapies in wet ARMD patients, and the researchers observed that cells expressing CFH polymorphisms displayed high levels of complement deposits, an effect that was exacerbated by VEGF antagonism (see the accompanying image). These findings support a link between VEGF signaling and complement activation that may explain inadequate outcomes of anti-VEGF therapy in some wet ARMD patients.

nephrology

VEGF regulates local inhibitory complement proteins in the eye and kidneyLindsay S. Keir, Rachel Firth, Lyndsey Aponik, Daniel Feitelberg, Susumu Sakimoto, Edith Aguilar, Gavin I. Welsh, Anna Richards, Yoshihiko Usui, Simon C. Satchell, Valeryia Kuzmuk, Richard J. Coward, Jonathan Goult, Katherine R. Bull, Ruchi Sharma, Kapil Bharti, Peter D. Westenskow, Iacovos P. Michael, Moin A. Saleem, and Martin Friedlander http://jci.me/86418

Prader-Willi syndrome (PWS) results from paternal deletion of a region encompassing multiple genes, including the noncoding RNA SNORD116. Individuals with PWS display hyperphagic obesity and neuroendocrine dysfunction, including abnormally low levels of growth hormone (GH) and insulin and high levels of the “hunger hormone” ghrelin. Lisa Cole Burnett and colleagues observed that the expression of two genes involved in prohormone processing, Nhlh2 and Pcsk1, are downregulated in PWS iPSC-derived neurons and in hypothalami of mice segregating for a paternal deletion of

endocrinology

Defective prohormone processing contributes to neuroendocrine dysfunction in Prader-Willi syndrome

Snord116 (Snord116p–/m+ mice). These mice recapitulate many of the neuroendocrine and behavioral phenotypes of patients with PWS. The authors showed that Snord116p–/m+ mice also displayed functional defects in proinsulin, proGH-releasing hormone, and proghrelin processing that were linked to reductions in the protein product of Pcsk1, the prohormone convertase PC1. In the accompanying Commen-tary, Joseph Polex-Wolf, Giles Yeo, and Stephen O’Rahilly discuss the implication that PC1 deficiency is a mechanism underlying the major neuroendocrine phenotypes of PWS.

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndromeLisa C. Burnett, Charles A. LeDuc, Carlos R. Sulsona, Daniel Paull, Richard Rausch, Sanaa Eddiry, Jayne F. Martin Carli, Michael V. Morabito, Alicja A. Skowronski, Gabriela Hubner, Matthew Zimmer, Liheng Wang, Robert Day, Brynn Levy, Ilene Fennoy, Beatrice Dubern, Christine Poitou, Karine Clement, Merlin G. Butler, Michael Rosenbaum, Jean Pierre Salles, Maithe Tauber, Daniel J. Driscoll, Dieter Egli, and Rudolph L. Leibel http://jci.me.org/88648

Related CommentaryImpaired prohormone processing: a grand unified theory for features of Prader-Willi syndrome?Joseph Polex-Wolf, Giles S.H. Yeo, and Stephen O’Rahilly http://jci.me.org/91307

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JCI | Research: Editor’s picks

Hippo signaling suppresses liver tumor formation through distinct molecular networksThe pathways that control cell proliferation and survival in the liver are tightly regulated, and mutations in multiple pathways have been linked to the development of hepatocellular carcinoma (HCC). Understanding how these pathways prevent tumor initia-tion in normal cells is a key step to improving the prevention and treatment of HCC. Work by Wantae Kim and colleagues determined that Hippo signaling interacts with STAT3, Wnt/β-catenin, and Notch signaling to produce pathway-distinct effects on liver tumor formation. Deletion of the mammalian Hippo kinases Mst1 and Mst2 in mouse livers led to the formation of a positive feedback loop between Notch and Yes-associated protein/tafazzin (YAP/TAZ), which promoted tumor initiation. Wnt/β-catenin signaling repressed tumor progression through these pathways by inhibiting Notch signaling (see the accompanying image). In contrast, STAT3 activation was not required for tumor formation in the absence of MST1/2. These findings provide important insights into how Hippo signaling interacts with distinct mutations to suppress or promote HCC formation.

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesisWantae Kim, Sanjoy Kumar Khan, Jelena Gvozdenovic-Jeremic, Youngeun Kim, Jason Dahlman, Hanjun Kim, Ogyi Park, Tohru Ishitani, Eek-hoon Jho, Bin Gao, and Yingzi Yang http://jci.me/88486

oncology

Metformin regulates aberrant mitochondrial metabolism in Li-Fraumeni syndrome

Inhibiting integrin α5β1 mitigates hyperresponsiveness in allergic airway contractionWhile preventive immune strategies can help to control asthma, there is still a pressing need for therapeutics to treat airway constriction during acute asthmatic responses. Prior work suggests that mast cell chymase and its murine ortholog mMCP-4 can inhibit tracheal ring contraction, and a deeper understanding of chymase-associated pathways may identify targets for treating airway hyperresponsiveness in asthma. Aparna Sundaram and coworkers examined the mechanisms by which chymase regulates the response of human bronchial rings to cytokine treatment. They determined that chymase cleaves the matrix protein fibronectin, inhibiting cellular adhesion in smooth muscle cells. Integrin α5β1 was the essential mediator of fibronectin-mediated adhesion, and inhibitors of α5β1 reduced allergen-induced bronchoconstric-tion and functioned synergistically with β-adrenergic agonists. This work suggests that α5β1 is a potential target for treating airway hyperresponsiveness in severe asthma.

Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthmaAparna Sundaram, Chun Chen, Amin Khalifeh-Soltani, Amha Atakilit, Xin Ren, Wenli Qiu, Hyunil Jo, William DeGrado, Xiaozhu Huang, and Dean Sheppard http://jci.me/88555

Li-Fraumeni syndrome (LFS) is an inherited disorder associated with increased predisposition to a number of cancers. LFS patients have germline mutations in the gene encoding p53 that increase mitochondrial respiration, but it is unclear whether alterations in mitochondrial metabolism influence tumorigenesis. Ping-yuan Wang, Jie Li, and colleagues observed that metformin treatment inhibited mitochondrial function in a mouse model

of LFS, resulting in decreased tumor formation and increased survival time. Moreover, in a pilot study, treating LFS patients with metformin led to similar inhibition of mitochondrial metabolism and activation of antiproliferation signaling. The finding that metformin, an FDA-approved diabetes medication, can ameliorate aberrant mitochondrial metabolism suggests that it has potential as a cancer prevention strategy in LFS patients.

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndromePing-yuan Wang, Jie Li, Farzana L. Walcott, Ju-Gyeong Kang, Matthew F. Starost, S. Lalith Talagala, Jie Zhuang, Ji-Hoon Park, Rebecca D. Huffstutler, Christina M. Bryla, Phuong L. Mai, Michael Pollak, Christina M. Annunziata, Sharon A. Savage, Antonio Tito Fojo, and Paul M. Hwang http://jci.me/88668

muscle biology

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JCI | Research: Editor’s picks

Longer red blood cell storage linked to worse transfusion outcomesConcerns about the risks of prolonged red blood cell storage have led to policy changes in some countries that limit storage to five weeks or less prior to transfusion. However, in the United States, current policies allow red cells to be stored for up to six weeks. In a clinical trial, Francesca Rapido and colleagues examined the outcomes of autologous transfusions into healthy volunteers after storage durations of one to six weeks. Participants who received transfusions of red cells that had been stored for six weeks displayed increased signs of extravascular hemolysis compared with patients receiving cells stored for one to five weeks. In the accompanying Commentary, Janet Lee and Daniel Kim-Shapiro discuss the need to further evaluate harmful outcomes of stored blood transfusion and the case for limiting the maximal storage period for red cells to five weeks or less.

Prolonged red cell storage before transfusion increases extravascular hemolysisFrancesca Rapido, Gary M. Brittenham, Sheila Bandyopadhyay, Francesca La Carpia, Camilla L’Acqua, Donald J. McMahon, Abdelhadi Rebbaa, Boguslaw S. Wojczyk, Jane Netterwald, Hangli Wang, Joseph Schwartz, Andrew Eisenberger, Mark Soffing, Randy Yeh, Chaitanya Divgi, Yelena Z. Ginzburg, Beth H. Shaz, Sujit Sheth, Richard O. Francis, Steven L. Spitalnik, and Eldad A. Hod http://jci.me/90837

Related Commentary Stored blood: how old is too old?Janet S. Lee and Daniel B. Kim-Shapiro http://jci.me/91309

Phagocytic myofibroblasts clear damage after myocardial infarctionAfter myocardial infarction, oxygen and nutrient shortages kill cardiomyo-cytes, which generate inflammatory responses as they leak cellular contents. Dead cells are rapidly engulfed to limit secondary damage to the affected area, but the processes responsible for engulfment are not fully described. Michio Nakaya and coworkers discovered a population of phagocytic cardiac myofibro-blasts that secrete an epidermal growth factor, MFG-E8, to promote engulfment of dead cardiomyocytes in a mouse model of myocardial infarction (see the accompanying image). Increased accumulation of dead cardiomyocytes and inflammatory responses observed in MFG-E8–deficient mice were associated with reduced survival after cardiac infarction. These findings identify MFG-E8 as a potential therapeutic target for improving recovery after myocardial infarction.

Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarctionMichio Nakaya, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono, Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, and Hitoshi Kurose http://jci.me/83822

cardiology hematology

Differential inflammatory responses underlie sex disparity in cardiovascular functionSubstantial differences in cardiovascular disease incidence between men and premenopausal women have been attributed to the cardioprotective effect of ovarian hormones, particularly estrogen. Although inflammation exacerbates the development of cardiovascular disease, the molecular pathways contributing to sex-based differences in inflammatory responses are not fully described. Two clinical studies performed by Krishnaraj Rathod and colleagues evaluated inflammation and vascular function in healthy men and women after induction of systemic or localized inflammation. In the first study, they observed that inflammatory and vascular responses in female subjects were less sensitive to the effects of typhoid vaccine–induced systemic inflammation than male subjects. In the second study,

cantharidin-induced blisters resolved more quickly in female subjects, which was associated with enhancement of the D-resolvin pathway. The authors proposed that accelerated resolution of inflammation in women contrib-utes, at least in part, to sex differences in cardiovascular function.

Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humansKrishnaraj S. Rathod, Vikas Kapil, Shanti Velmurugan, Rayomand S. Khambata, Umme Siddique, Saima Khan, Sven Van Eijl, Lorna C. Gee, Jascharanpreet Bansal, Kavi Pitrola, Christopher Shaw, Fulvio D’Acquisto, Romain A. Colas, Federica Marelli-Berg, Jesmond Dalli, and Amrita Ahluwalia http://jci.me.org/89429

vascular biology

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JCI | Research: Editor’s picks

Targeting MyD88 signaling prevents fibrotic responses to kidney injuryFibrotic disease can develop in any tissue, often in response to toxic or ischemic tissue injury. In the fibrotic kidney, a large number of myofibroblasts derive from pericytes. Irina Leaf and coworkers investi-gated a dominant innate immune program activated in human kidney injury and discovered that it is activated predominantly in pericytes. A central node in this program is the myeloid differentiation response protein MyD88. Unexpectedly, they found that MyD88 controls both innate immune and fibrogenic responses in pericytes. Ablating MyD88 or blocking its downstream signaling using a novel inhibitor of IRAK4 protected against fibrotic responses in a mouse model of kidney injury and preserved organ function (see the accompanying image). Targeting MyD88-dependent pathways is a promising approach to preventing fibrotic and inflammatory responses to injury.

High-maintenance β cell identity requires continuous gene activation and suppressionRecent evidence indicates that adverse metabolic conditions can compromise the differentiated state of insulin-producing β cells, but the mechanisms that sustain adult β cell identity and function are not completely described. This month in the JCI, three studies describe how transcription factors that influence β cell development also act to maintain adult β cell identity. Avital Swisa and colleagues found that expression of PAX6 is downregulated in diabetic mice and is central to activating β cell–specific genes and repressing genes typical of other islet cell types, including the fetal hormone ghrelin. A second study, by Benjamin Ediger and coworkers, determined that LIM domain–binding protein 1 (LDB1) also maintains the differentiated state of mature β cells by promoting the expression of genes associated with β cell identity and inhibiting non–β cell gene programs. Finally, work by Giselle Domínguez Gutiérrez and labmates showed that the developmental regulatory factor NK2 homeobox 2 (NKX2.2) continuously suppresses non–β cell genetic programs to maintain adult β cell identity and function. In the absence of NKX2.2, β cells acquired features of other endocrine cell types (see the associated image). In the accompany-ing Commentary, Peter Thompson and Anil Bhushan highlight the tenuous nature of β cell differentiation and emphasize the concept that plasticity in β cell identity and function forms the basis for defective insulin secretion in diabetes and other disorders.

Related ResearchPAX6 maintains β cell identity by repressing genes of alternative islet cell typesAvital Swisa, Dana Avrahami, Noa Eden, Jia Zhang, Eseye Feleke, Tehila Dahan, Yamit Cohen-Tayar, Miri Stolovich-Rain, Klaus H. Kaestner, Benjamin Glaser, Ruth Ashery-Padan, and Yuval Dor http://jci.me/88015

LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cellsBenjamin N. Ediger, Hee-Woong Lim, Christine Juliana, David N. Groff, LaQueena T. Williams, Giselle Dominguez, Jin-Hua Liu, Brandon L. Taylor, Erik R. Walp, Vasumathi Kameswaran, Juxiang Yang, Chengyang Liu, Chad S. Hunter, Klaus H. Kaestner, Ali Naji, Changhong Li, Maike Sander, Roland Stein, Lori Sussel, Kyoung-Jae Won, Catherine Lee May, and Doris A. Stoffers http://jci.me/88016

Pancreatic β cell identity requires continual repression of non–β cell programsGiselle Domínguez Gutiérrez, Aaron S. Bender, Vincenzo Cirulli, Teresa L. Mastracci,

Stephen M. Kelly, Aristotelis Tsirigos, Klaus H. Kaestner, and Lori Sussel http://jci.me/88017

Related Commentaryβ Cells led astray by transcription factors and the company they keepPeter Thompson and Anil Bhushan http://jci.me/91304

metabolism

inflammation

Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injuryIrina A. Leaf, Shunsaku Nakagawa, Bryce G. Johnson, Jin Joo Cha, Kristen Mittelsteadt, Kevin M. Guckian, Ivan G. Gomez, William A. Altemeier, and Jeremy S. Duffield http://jci.me/87532

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JCI | Research: Editor’s picks

neuroscience

aids/hiv

Interfering with interferon type I signaling boosts HIV-1 suppressionAlthough combined antiretroviral therapy (cART) can effectively suppress HIV-1 replication, some HIV-1–positive individuals still experience chronic immune activation and exhaustion that can accelerate disease progression. This chronic immune activation has been linked to persistent interferon type I (IFN-I) signaling. Now, two studies have demonstrated that blocking IFN-I signaling can augment cART efficacy in humanized mouse models of HIV-1 infection. Anjie Zhen and labmates treated HIV-1–infected mice with an antibody to block human IFN receptor 2 and observed reduced signs of T cell exhaustion and viral load. Liang Cheng and Jianping Ma developed an antibody to target the human IFN-α/β receptor, which reversed immune hyperactivation in the mouse model. In

Microglial TGF-β1 mediates repair and recovery after intracerebral hemorrhageIntracerebral hemorrhage (ICH) and other acute brain injuries cause rapid inflammatory responses in the brain that activate resident microglia and immune responses. These inflammatory and immune responses contribute to risk of secondary injury after ICH. Roslyn Taylor and labmates examined the activation profile of microglia in the early proinflammatory and later resolution phases of inflammation in a mouse model of ICH. They determined that the resolution phase of inflammation coincides with increases in TGF-β1 pathway activation in microglia (see the accompanying image). Treating mice with TGF-β1 immediately after ICH improved motor function. Further, they found that patients who displayed early increases in plasma TGF-β1 experienced better outcomes 3 months after the ICH episode. Together, these results indicated that activation of the TGF-β1 pathway mitigates microglia-mediated inflammation after injury, pointing to TGF-β1 treatment as a potential approach for preventing further damage after acute brain injury.

TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhageRoslyn A. Taylor, Che-Feng Chang, Brittany A. Goods, Matthew D. Hammond, Brian Mac Grory, Youxi Ai, Arthur F. Steinschneider, Stephen C. Renfroe, Michael H. Askenase, Louise D. McCullough, Scott E. Kasner, Michael T. Mullen, David A. Hafler, J. Christopher Love, and Lauren H. Sansing http://jci.me.org/88647

both studies, blockade of IFN-I signaling synergized with cART treatment in HIV-1–infected mice, leading to enhanced T cell responses and lower viral load. In the accompanying Commen-tary, Steven Deeks, Pamela Odorizzi, and Rafick Sekaly suggest that further evaluation of IFN-I blockade as a supplement to cART is warranted.

Related ResearchTargeting type I interferon–mediated activation restores immune function in chronic HIV infectionAnjie Zhen, Valerie Rezek, Cindy Youn, Brianna Lam, Nelson Chang, Jonathan Rick, Mayra Carrillo, Heather Martin, Saro Kasparian, Philip Syed, Nicholas Rice, David G. Brooks, and Scott G. Kitchen http://jci.me/89488

Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirsLiang Cheng, Jianping Ma, Jingyun Li, Dan Li, Guangming Li, Feng Li, Qing Zhang, Haisheng Yu, Fumihiko Yasui, Chaobaihui Ye, Li-Chung Tsao, Zhiyuan Hu, Lishan Su, and Liguo Zhang http://jci.me/90745

Related CommentaryThe interferon paradox: can inhibiting an antiviral mechanism advance an HIV cure?Steven G. Deeks, Pamela M. Odorizzi, and Rafick-Pierre Sekaly http://jci.me/91916

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JCI | Features

conversations with giants in medicine

Bruce AlbertsThough Bruce Alberts is well known for his work on the biochemistry of DNA replication and as the editor-in-chief of Science, he is also recognizable as the author of the seminal biology textbook Molecular Biology of the Cell. Alberts served as the president of the National Academy of Sciences for over a decade and is currently a professor at the University of California, San Francisco. This year, his dedication to advancing science policy and education was recognized with the Lasker-Koshland Special Achievement Award. JCI Editor at Large Ushma Neill sat down with Alberts to talk about how his background in science shaped his later work as an educator and leader in science policy. They also discuss the challenges of improving science education through writing, editing, and policy making. http://jci.me/91072

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JCI Review Series

Metabolism and inflammationSeries Editors: Alan R. Saltiel and Jerrold M. Olefsky

Understanding the interactions between inflammation and metabolic dysfunctionMetabolic syndrome comprises a constellation of conditions including central obesity, glucose intolerance, and dyslipidemia. These conditions enhance the risk of type 2 diabetes, cardiovascular disease, fatty liver/cir-rhosis, hypertension, and cancer. The finding over 20 years ago that the inflammatory mediator TNF-α is overexpressed in adipose tissue funda-mentally changed our understanding of obesity and metabolic syndrome. We now know that metabolic syndrome in humans is characterized by chronic low-grade inflammation in multiple organs, and we are now begin-ning to delineate the mechanisms by which inflammation and metabolism influence each other. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a proinflam-matory phenotype.

Inflammatory mechanisms linking obesity and metabolic diseaseAlan R. Saltiel and Jerrold M. Olefsky http://jci.me/92035

Alan R. Saltiel, PhD, is the Director of the Institute for Diabetes and Metabolic Health at the University of California, San Diego, a member of the National Academy of Medicine, a fellow of the American Asso-ciation for the Advancement of Science, and a recipient of the American Diabetes Association’s Rosalyn Yalow Research and Development Award and the John J. Abel Award from the American Society for Phar-macology and Experimental Therapeutics. His laboratory investigates the molecular events involved in the regulation of glucose uptake and storage, with a focus on the mechanisms that underlie the action of insulin and the links between obesity and diabetes.

Jerrold M. Olefsky, MD, is Associate Dean for Scientific Affairs and Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism in the Department of Medicine at the University of California, San Diego, and a recipient of the American Diabetes Association’s Banting Medal for Scientific Achievement. His laboratory investigates the molecular mechanisms of insulin and growth factor action in multiple tissues, with an emphasis on the insulin signaling pathway that stimulates glucose transport.

Role of innate and adaptive immunity in obesity-associated metabolic diseaseTracey McLaughlin, Shelley E. Ackerman, Lei Shen, and Edgar Engleman http://jci.me/88876

Islet inflammation in type 2 diabetes and physiologyKosei Eguchi and Ryozo Nagai http://jci.me/88877

Hypothalamic inflammation in obesity and metabolic diseaseAlexander Jais and Jens C. Brüning http://jci.me/88878

Immunologic impact of the intestine in metabolic diseaseDaniel A. Winer, Shawn Winer, Helen J. Dranse, and Tony K.T. Lam http://jci.me/88879

Skeletal muscle inflammation and insulin resistance in obesityHuaizhu Wu and Christie M. Ballantyne http://jci.me/88880

Liver inflammation and fibrosisYukinori Koyama and David A. Brenner http://jci.me/88881

The initiation of metabolic inflammation in childhood obesityKanakadurga Singer and Carey N. Lumeng http://jci.me/88882

The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesisClair Crewe, Yu Aaron An, and Philipp E. Scherer http://jci.me/88883

Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular riskAllison B. Goldfine and Steven E. Shoelson http://jci.me/88884

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aids/hivTargeting type I interferon–mediated activation restores immune function in chronic HIV infection p. 6Anjie Zhen, Valerie Rezek, Cindy Youn, Brianna Lam, Nelson Chang, Jonathan Rick, Mayra Carrillo, Heather Martin, Saro Kasparian, Philip Syed, Nicholas Rice, David G. Brooks, and Scott G. Kitchen http://jci.me/89488

Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs p. 6Liang Cheng, Jianping Ma, Jingyun Li, Dan Li, Guangming Li, Feng Li, Qing Zhang, Haisheng Yu, Fumihiko Yasui, Chaobaihui Ye, Li-Chung Tsao, Zhiyuan Hu, Lishan Su, and Liguo Zhang http://jci.me/90745

cardiologyCardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction p. 4Michio Nakaya, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono, Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, and Hitoshi Kurose http://jci.me/83822

The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophyBernard Thienpont, Jan Magnus Aronsen, Emma Louise Robinson, Hanneke Okkenhaug, Elena Loche, Arianna Ferrini, Patrick Brien, Kanar Alkass, Antonio Tomasso, Asmita Agrawal, Olaf Bergmann, Ivar Sjaastad, Wolf Reik, and Hywel Llewelyn Roderick http://jci.me/88353

cell biologyEpithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11 p. 1Xiaochao Tan, Priyam Banerjee, Hou-Fu Guo, Stephen Ireland, Daniela Pankova, Young-ho Ahn, Irodotos Michail Nikolaidis, Xin Liu, Yanbin Zhao, Yongming Xue, Alan R. Burns, Jonathon Roybal, Don L. Gibbons, Tomasz Zal, Chad J. Creighton, Daniel Ungar, Yanzhuang Wang, and Jonathan M. Kurie http://jci.me/88736

dermatologyTuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activationJuxiang Cao, Magdalena E. Tyburczy, Joel Moss, Thomas N. Darling, Hans R. Widlund, and David J. Kwiatkowski http://jci.me/84262

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapyTrevor J. Cunningham, Mary Tabacchi, Jean-Pierre Eliane, Sara Moradi Tuchayi, Sindhu Manivasagam, Hengameh Mirzaalian, Ahu Turkoz, Raphael Kopan, Andras Schaffer, Arturo P. Saavedra, Michael Wallendorf, Lynn A. Cornelius, and Shadmehr Demehri http://jci.me/89820

endocrinologyDeficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome p. 2Lisa C. Burnett, Charles A. LeDuc, Carlos R. Sulsona, Daniel Paull, Richard Rausch, Sanaa Eddiry, Jayne F. Martin Carli, Michael V. Morabito, Alicja A. Skowronski, Gabriela Hubner, Matthew Zimmer, Liheng Wang, Robert Day, Brynn Levy, Ilene Fennoy, Beatrice Dubern, Christine Poitou, Karine Clement, Merlin G. Butler, Michael Rosenbaum, Jean Pierre Salles, Maithe Tauber, Daniel J. Driscoll, Dieter Egli, and Rudolph L. Leibel http://jci.me/88648

Current research articles

Actinic keratosis

Cardiac myofibroblast engulfment

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hematologyProlonged red cell storage before transfusion increases extravascular hemolysis p. 4Francesca Rapido, Gary M. Brittenham, Sheila Bandyopadhyay, Francesca La Carpia, Camilla L’Acqua, Donald J. McMahon, Abdelhadi Rebbaa, Boguslaw S. Wojczyk, Jane Netterwald, Hangli Wang, Joseph Schwartz, Andrew Eisenberger, Mark Soffing, Randy Yeh, Chaitanya Divgi, Yelena Z. Ginzburg, Beth H. Shaz, Sujit Sheth, Richard O. Francis, Steven L. Spitalnik, and Eldad A. Hod http://jci.me/90837

immunologyBiallelic mutations in IRF8 impair human NK cell maturation and functionEmily M. Mace, Venetia Bigley, Justin T. Gunesch, Ivan K. Chinn, Laura S. Angelo, Matthew A. Care, Sheetal Maisuria, Michael D. Keller, Sumihito Togi, Levi B. Watkin, David F. LaRosa, Shalini N. Jhangiani, Donna M. Muzny, Asbjørg Stray-Pedersen, Zeynep Coban Akdemir, Jansen B. Smith, Mayra Hernández-Sanabria, Duy T. Le, Graham D. Hogg, Tram N. Cao, Aharon G. Freud, Eva P. Szymanski, Sinisa Savic, Matthew Collin, Andrew J. Cant, Richard A. Gibbs, Steven M. Holland, Michael A. Caligiuri, Keiko Ozato, Silke Paust, Gina M. Doody, James R. Lupski, and Jordan S. Orange http://jci.me/86276

inflammationPericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury p. 5Irina A. Leaf, Shunsaku Nakagawa, Bryce G. Johnson, Jin Joo Cha, Kristen Mittelsteadt, Kevin M. Guckian, Ivan G. Gomez, William A. Altemeier, and Jeremy S. Duffield http://jci.me/87532

metabolismPAX6 maintains β cell identity by repressing genes of alternative islet cell types p. 5Avital Swisa, Dana Avrahami, Noa Eden, Jia Zhang, Eseye Feleke, Tehila Dahan, Yamit Cohen-Tayar, Miri Stolovich-Rain, Klaus H. Kaestner, Benjamin Glaser, Ruth Ashery-Padan, and Yuval Dor http://jci.me/88015

LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cells p. 5Benjamin N. Ediger, Hee-Woong Lim, Christine Juliana, David N. Groff, LaQueena T. Williams, Giselle Dominguez, Jin-Hua Liu, Brandon L. Taylor, Erik R. Walp, Vasumathi Kameswaran, Juxiang Yang, Chengyang Liu, Chad S. Hunter, Klaus H. Kaestner, Ali Naji, Changhong Li, Maike Sander, Roland Stein, Lori Sussel, Kyoung-Jae Won, Catherine Lee May, and Doris A. Stoffers http://jci.me/88016

Pancreatic β cell identity requires continual repression of non–β cell programs p. 5Giselle Domínguez Gutiérrez, Aaron S. Bender, Vincenzo Cirulli, Teresa L. Mastracci, Stephen M. Kelly, Aristotelis Tsirigos, Klaus H. Kaestner, and Lori Sussel http://jci.me/88017

muscle biologyTargeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma p. 3Aparna Sundaram, Chun Chen, Amin Khalifeh-Soltani, Amha Atakilit, Xin Ren, Wenli Qiu, Hyunil Jo, William DeGrado, Xiaozhu Huang, and Dean Sheppard http://jci.me/88555

Current research articles

Pericyte inflammation

Pancreatic islet

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nephrologyVEGF regulates local inhibitory complement proteins in the eye and kidney p. 2Lindsay S. Keir, Rachel Firth, Lyndsey Aponik, Daniel Feitelberg, Susumu Sakimoto, Edith Aguilar, Gavin I. Welsh, Anna Richards, Yoshihiko Usui, Simon C. Satchell, Valeryia Kuzmuk, Richard J. Coward, Jonathan Goult, Katherine R. Bull, Ruchi Sharma, Kapil Bharti, Peter D. Westenskow, Iacovos P. Michael, Moin A. Saleem, and Martin Friedlander http://jci.me/86418

neuroscienceTGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage p. 6Roslyn A. Taylor, Che-Feng Chang, Brittany A. Goods, Matthew D. Hammond, Brian Mac Grory, Youxi Ai, Arthur F. Steinschneider, Stephen C. Renfroe, Michael H. Askenase, Louise D. McCullough, Scott E. Kasner, Michael T. Mullen, David A. Hafler, J. Christopher Love, and Lauren H. Sansing http://jci.me/88647

oncologyDual modulation of MCL-1 and mTOR determines the response to sunitinibMohamed Elgendy, Amal Kamal Abdel-Aziz, Salvatore Lorenzo Renne, Viviana Bornaghi, Giuseppe Procopio, Maurizio Colecchia, Ravindran Kanesvaran, Chee Keong Toh, Daniela Bossi, Isabella Pallavicini, Jose Luis Perez-Gracia, Maria Dolores Lozano, Valeria Giandomenico, Ciro Mercurio, Luisa Lanfrancone, Nicola Fazio, Franco Nole, Bin Tean Teh, Giuseppe Renne, and Saverio Minucci http://jci.me/84386

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis p. 3Wantae Kim, Sanjoy Kumar Khan, Jelena Gvozdenovic-Jeremic, Youngeun Kim, Jason Dahlman, Hanjun Kim, Ogyi Park, Tohru Ishitani, Eek-hoon Jho, Bin Gao, and Yingzi Yang http://jci.me/88486

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome p. 3Ping-yuan Wang, Jie Li, Farzana L. Walcott, Ju-Gyeong Kang, Matthew F. Starost, S. Lalith Talagala, Jie Zhuang, Ji-Hoon Park, Rebecca D. Huffstutler, Christina M. Brylan, Phuong L. Mai, Michael Pollak, Christina M. Annuziata, Sharon A. Savage, Antonio Tito Fojo, and Paul M. Hwang http://jci.me/88668

Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapiesMihalis S. Kariolis, Yu Rebecca Miao, Anh Diep, Shannon E. Nash, Monica M. Olcina, Dadi Jiang, Douglas S. Jones II, Shiven Kapur, Irimpan I. Mathews, Albert C. Koong, Erinn B. Rankin, Jennifer R. Cochran, and Amato J. Giaccia http://jci.me/85610

vascular biologyAccelerated resolution of inflammation underlies sex differences in inflammatory responses in humans p. 4Krishnaraj S. Rathod, Vikas Kapil, Shanti Velmurugan, Rayomand S. Khambata, Umme Siddique, Saima Khan, Sven Van Eijl, Lorna C. Gee, Jascharanpreet Bansal, Kavi Pitrola, Christopher Shaw, Fulvio D’Acquisto, Romain A. Colas, Federica Marelli-Berg, Jesmond Dalli, and Amrita Ahluwalia http://jci.me/89429

Complement in kidney

DNA damage

Liver tumorigenesis

HCT116 xenograft

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JCI Insight is a new peer-reviewed journal dedicated to biomedical research, ranging from preclinical to clinical studies.More information: http://jci.me/insinf or editors@insight.jci.org

Editor’s picks

hepatology

A critical role for HDL/sphingosine-1-phosphate receptor-1 signaling after liver injuryLiver injury is a leading cause of morbidity and mortality, but could potentially be treated with strategies to stimulate liver regeneration. Disruption of the crosstalk between hepatocytes and the liver sinusoidal vascular endothelium leads to impaired regeneration and maladaptive healing characterized by fibrosis. Using three murine models of liver regeneration and repair, Bi-Sen Ding and colleagues show that endothelial sphingosine-1-phosphate (S1P) bound to HDL (HDL-S1P) induces liver regeneration and attenuates fibrosis. After a partial hepatectomy, mice lacking HDL-S1P exhibited impaired regeneration, aberrant vascular remodeling, thrombosis, and perisinusoidal fibrosis (see the accompanying image). Conversely, elevation of plasma HDL-S1P levels or treatment with an S1P receptor-1 (S1P1) agonist enhanced liver regeneration. These findings suggest that therapeutic strategies to stimulate S1P1 signaling may ameliorate liver fibrosis.

HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liverBi-Sen Ding, Catherine H. Liu, Yue Sun, Yutian Chen, Steven L. Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R. Schwab, Shahin Rafii, and Timothy Hla http://jci.me/87058

The β-adrenergic receptor mediates hypoxia sensing

vascular biology

demonstrate that β-ARs mediate molecular and physiological responses to hypoxia.

Hypoxia sensing through β-adrenergic receptorsHoi I. Cheong, Kewal Asosingh, Olivia R. Stephens, Kimberly A. Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R. Stark, Sathyamangla V. Naga Prasad, and Serpil C. Erzurum http://jci.me/90240

Tissue hypoxia induces a series of adaptive responses through the hypoxia-induced transcrip-tion factor HIF-1α to increase red blood cells and generate new blood vessels; however, the molecular mechanisms by which cells sense hypoxia are not entirely clear. Hoi Cheong and colleagues hypoth-esized that the β-adrenergic receptor (β-AR) mediates hypoxia sensing and is necessary for HIF-1α accumulation. They found that treatment of mice with a β-AR antagonist (beta blocker) impaired hypoxia-induced HIF-1α accumulation in

the kidney and attenuated erythropoietin production and erythropoiesis. Beta blocker treatment of human endothelial cells also impaired hypoxia-induced HIF-1α accumulation and downstream gene regulation. Mechanistically, Cheong and colleagues showed that hypoxia induces changes in phosphorylation of a specific set of residues on β-ARs under hypoxic conditions; mutation of GPCR kinase (GRK) phosphorylation sites or inhibition of GRK abrogated hypoxia-induced HIF-1α accumulation. These studies

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 7 13

JCI Insight | Editor’s picks

clinical medicine

oncology

Tracking changes in tumor-infiltrating lymphocyte behavior

Early immunological changes in human liver transplant ischemia/reperfusion injuryOrthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. Ischemia/reperfusion injury (IRI) can compromise allograft survival; however, our understanding of the underlying immunological mechanisms is limited. Rebecca Sosa and colleagues conducted a longitudinal study in 53 OLT patients to measure the expression of 38 cytokines, chemokines, and growth factors in the circulating systemic blood before and after transplant and in the portal blood before and after reperfusion, as well as the expression of cytokine receptor genes in donor allograft biopsies before and after transplant. They then analyzed the relationship between cytokine expression and standard clinical liver function tests after transplant and biopsy-proven IRI (see the accompanying image). They identified 14 cytokines that were increased in the systemic or portal blood of patients with biopsy-proven IRI and expression of 10 cognate receptors for these cytokines in the donor organs. These findings will help to identify immunological mechanisms that underlie IRI and may be useful in identifying at-risk patients.

Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantationRebecca A. Sosa, Ali Zarrinpar, Maura Rossetti, Charles R. Lassman, Bita V. Naini, Nakul Datta, Ping Rao, Nicholas Harre, Ying Zheng, Roberto Spreafico, Alexander Hoffmann, Ronald W. Busuttil, David W. Gjertson, Yuan Zhai, Jerzy W. Kupiec-Weglinski, and Elaine F. Reed http://jci.me/89679

Signals within the tumor microenvironment tolerize the tumor-infiltrating lymphocytes (TILs), making them unable to eliminate the tumor. Tolerized TILs express elevated levels of exhaustion markers such as inhibitory receptors and are unable to make effector cytokines, but the timing and sequence of events in this tolerization process are unclear. Bijan Boldajipour and colleagues used high-resolution intravital imaging to track the behavior of TILs in an autochthonus murine model of breast cancer to

understand the relationship between cellular behavior and tolerization. They found that TIL behavior began to change within the first few days of tumor residence when TILs arrested on tumor-associ-ated macrophages. Within 10 days, the cells became motile, but T cell receptor signaling appeared to be absent. Unexpectedly, many of these cells underwent active cell division (see the accompanying image), which was at least partially reliant on IL-15. These data indicate that TILs undergo sequential

reprogramming by the tumor microenvironment that renders them antigen insensitive and maintains them in a dysfunctional state.

Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokineBijan Boldajipour, Amanda Nelson, and Matthew F. Krummel http://jci.me/89289

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JCI Insight | Editor’s picks

pulmonology

Due to the increasing evidence that the respiratory epithelium plays a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), Yan Xu, Takako Mizuno, and colleagues performed single-cell RNA sequencing in epithelial cells isolated from the lungs of IPF patients and healthy controls to identify disease-relevant processes. Compared with normal lung epithelial cells, which were characterized as highly differentiated alveolar type 2 cells, IPF epithelial cells could be divided into three distinct subsets that included airway basal and goblet cells and an atypical transitional cell. Further, many IPF epithelial cells exhibited indeterminate states of differentiation that were not observed in normal lung (see

the accompanying image). Moreover, several signaling pathways were aberrantly activated in IPF epithelium, including TGF-β, HIPPO/YAP, p53, WNT, and AKT/PI3K. These data identify processes and pathways that may underlie IPF pathology.

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosisYan Xu, Takako Mizuno, Anusha Sridharan, Yina Du, Minzhe Guo, Jie Tang, Kathryn A. Wikenheiser-Brokamp, Anne-Karina T. Perl, Vincent A. Funari, Jason J. Gokey, Barry R. Stripp, and Jeffrey A. Whitsett http://jci.me.org/90558

Single-cell RNA sequencing identifies epithelial alterations in idiopathic pulmonary fibrosis

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j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 7 15

Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic diseaseNaoki Nakagawa, Luke Barron, Ivan G. Gomez, Bryce G. Johnson, Allie M. Roach, Sei Kameoka, Richard M. Jack, Mark L. Lupher Jr., Sina A. Gharib, and Jeremy S. Duffield http://jci.me/87446

B cell repertoire expansion occurs in meningeal ectopic lymphoid tissueKlaus Lehmann-Horn, Sheng-zhi Wang, Sharon A. Sagan, Scott S. Zamvil, and H.-Christian von Büdingen http://jci.me/87234

IFN-ε protects primary macrophages against HIV infectionCarley Tasker, Selvakumar Subbian, Pan Gao, Jennifer Couret, Carly Levine, Saleena Ghanny, Patricia Soteropoulos, Xilin Zhao, Nathaniel Landau, Wuyuan Lu, and Theresa L. Chang http://jci.me/88255

Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaquesKan Luo, Hua-Xin Liao, Ruijun Zhang, David Easterhoff, Kevin Wiehe, Thaddeus C. Gurley, Lawrence C. Armand, Ashley A. Allen, Tarra A. Von Holle, Dawn J. Marshall, John F. Whitesides, Jamie Pritchett, Andrew Foulger, Giovanna Hernandez, Robert Parks, Krissey E. Lloyd, Christina Stolarchuk, Sheetal Sawant, Jessica Peel, Nicole L. Yates, Erika Dunford, Sabrina Arora, Amy Wang, Cindy M. Bowman, Laura L. Sutherland, Richard M. Scearce, Shi-Mao Xia, Mattia Bonsignori, Justin Pollara, R. Whitney Edwards, Sampa Santra, Norman L. Letvin, James Tartaglia, Donald Francis, Faruk Sinangil, Carter Lee, Jaranit Kaewkungwal, Sorachai Nitayaphan, Punnee Pitisuttithum, Supachai Rerks-Ngarm, Nelson L. Michael, Jerome H. Kim, S. Munir Alam, Nathan A. Vandergrift, Guido Ferrari, David C. Montefiori, Georgia D. Tomaras, Barton F. Haynes, and. M. Anthony Moody http://jci.me/88522

Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetesHoward R. Seay, Erik Yusko, Stephanie J. Rothweiler, Lin Zhang, Amanda L. Posgai, Martha Campbell-Thompson, Marissa Vignali, Ryan O. Emerson, John S. Kaddis, Dave Ko, Maki Nakayama, Mia J. Smith, John C. Cambier, Alberto Pugliese, Mark A. Atkinson, Harlan S. Robins, and Todd M. Brusko http://jci.me/88242

Chorioretinal thinning in chronic kidney disease links to inflammation and endothelial dysfunctionCraig Balmforth, Job J.M.H. van Bragt, Titia Ruijs, James R. Cameron, Robert Kimmitt, Rebecca Moorhouse, Alicja Czopek, May Khei Hu, Peter J. Gallacher, James W. Dear, Shyamanga Borooah, Iain M. MacIntyre, Tom M.C. Pearson, Laura Willox, Dinesh Talwar, Muriel Tafflet, Christophe Roubeix, Florian Sennlaub, Siddharthan Chandran, Baljean Dhillon, David J. Webb, and Neeraj Dhaun http://jci.me/89173

Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine p. 13Bijan Boldajipour, Amanda Nelson, and Matthew F. Krummel http://jci.me/89289

IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humansFawaz Alzaid, Floriane Lagadec, Miguel Albuquerque, Raphaëlle Ballaire, Lucie Orliaguet, Isabelle Hainault, Corinne Blugeon, Sophie Lemoine, Agnès Lehuen, David G. Saliba, Irina A. Udalova, Valérie Paradis, Fabienne Foufelle, and Nicolas Venteclef http://jci.me/88689

Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation p. 13Rebecca A. Sosa, Ali Zarrinpar, Maura Rossetti, Charles R. Lassman, Bita V. Naini, Nakul Datta, Ping Rao, Nicholas Harre, Ying Zheng, Roberto Spreafico, Alexander Hoffmann, Ronald W. Busuttil, David W. Gjertson, Yuan Zhai, Jerzy W. Kupiec-Weglinski, and Elaine F. Reed http://jci.me/89679

Hepatic fibrosis

Pancreatic islet lymphocytes

Kidney fibrosis

Current research articles

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mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regenerationShailesh Agarwal, David Cholok, Shawn Loder, John Li, Christopher Breuler, Michael T. Chung, Hsiao Hsin Sung, Kavitha Ranganathan, Joseph Habbouche, James Drake, Joshua Peterson, Caitlin Priest, Shuli Li, Yuji Mishina, and Benjamin Levi http://jci.me/89805

Interleukin 6 regulates psoriasiform inflammation–associated thrombosisYunmei Wang, Jackelyn B. Golden, Yi Fritz, Xiufen Zhang, Doina Diaconu, Maya I. Camhi, Huiyun Gao, Sean M. Dawes, Xianying Xing, Santhi K. Ganesh, Johann E. Gudjonsson, Daniel I. Simon, Thomas S. McCormick, and Nicole L. Ward http://jci.me/89384

DNA methylation in lung cells is associated with asthma endotypes and genetic riskJessie Nicodemus-Johnson, Rachel A. Myers, Noburu J. Sakabe, Debora R. Sobreira, Douglas K. Hogarth, Edward T. Naureckas, Anne I. Sperling, Julian Solway, Steven R. White, Marcelo A. Nobrega, Dan L. Nicolae, Yoav Gilad, and Carole Ober http://jci.me/90151

Low-dose dasatinib rescues cardiac function in Noonan syndromeJae-Sung Yi, Yan Huang, Andrea T. Kwaczala, Ivana Y. Kuo, Barbara E. Ehrlich, Stuart G. Campbell, Frank J. Giordano, and Anton M. Bennett http://jci.me/90220

miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathwaysLingyin Ge, David M. Habiel, Phil M. Hansbro, Richard Y. Kim, Sina A. Gharib, Jeffery D. Edelman, Melanie Königshoff, Tanyalak Parimon, Rena Brauer, Ying Huang, Jenieke Allen, Dian Jiang, Adrianne A. Kurkciyan, Takako Mizuno, Barry R. Stripp, Paul W. Noble, Cory M. Hogaboam, and Peter Chen http://jci.me/90301

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis p. 14Yan Xu, Takako Mizuno, Anusha Sridharan, Yina Du, Minzhe Guo, Jie Tang, Kathryn A. Wikenheiser-Brokamp, Anne-Karina T. Perl, Vincent A. Funari, Jason J. Gokey, Barry R. Stripp, and Jeffrey A. Whitsett http://jci.me/90558

Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitisRyan E. Feaver, Banumathi K. Cole, Mark J. Lawson, Stephen A. Hoang, Svetlana Marukian, Brett R. Blackman, Robert A. Figler, Arun J. Sanyal, Brian R. Wamhoff, and Ajit Dash http://jci.me/90954

ATG16L1 governs placental infection risk and preterm birth in mice and womenBin Cao, Colin Macones, and Indira U. Mysorekar http://jci.me/86654

HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver p. 12Bi-Sen Ding, Catherine H. Liu, Yue Sun, Yutian Chen, Steven L. Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R. Schwab, Shahin Rafii, and Timothy Hla http://jci.me/87058

Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cellsChandra Sekhar Boddupalli, Noffar Bar, Krishna Kadaveru, Michael Krauthammer, Natopol Pornputtapong, Zifeng Mai, Stephan Ariyan, Deepak Narayan, Harriet Kluger, Yanhong Deng, Rakesh Verma, Rituparna Das, Antonella Bacchiocchi, Ruth Halaban, Mario Sznol, Madhav V. Dhodapkar, and Kavita M. Dhodapkar http://jci.me/88955

Psoriasiform inflammation

Lung fibrosis

Biliary epithelial injury

Current research articles

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 7 17

Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severityShane Lofgren, Monique Hinchcliff, Mary Carns, Tammara Wood, Kathleen Aren, Esperanza Arroyo, Peggie Cheung, Alex Kuo, Antonia Valenzuela, Anna Haemel, Paul J. Wolters, Jessica Gordon, Robert Spiera, Shervin Assassi, Francesco Boin, Lorinda Chung, David Fiorentino, Paul J. Utz, Michael Whitfield, and Purvesh Khatri http://jci.me/89073

Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndromeØystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E. Dyrstad, Kine Alme, Ingrid G. Rekeland, Dipak Sapkota, Gro V. Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E. Gotaas, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M. Ueland, Olav Dahl, and Karl J. Tronstad http://jci.me/89376

Inactivation of ABL kinases suppresses non–small cell lung cancer metastasisJing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, and Ann Marie Pendergast http://jci.me/89647

Hypoxia sensing through β-adrenergic receptors p. 12Hoi I. Cheong, Kewal Asosingh, Olivia R. Stephens, Kimberly A. Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R. Stark, Sathyamangla V. Naga Prasad, and Serpil C. Erzurum http://jci.me/90240

Disease modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscleDavid W. Hammers, Margaret M. Sleeper, Sean C. Forbes, Cora C. Coker, Michael R. Jirousek, Michael Zimmer, Glenn A. Walter, and H. Lee Sweeney http://jci.me/90341

Identifying the third dimension in 2D fluoroscopy to create 3D cardiac mapsJasbir Sra, David Krum, Indrajit Choudhuri, Barry Belanger, Mark Palma, Donald Brodnick, and Daniel B. Rowe http://jci.me/90453

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapyJiha Kim, Pedro Correa de Sampaio, Donna Marie Lundy, Qian Peng, Kurt W. Evans, Hikaru Sugimoto, Mihai Gagea, Yvonne Kienast, Nayra Soares do Amaral, Rafael Malagoli Rocha, Hans P. Eikesdal, Per Eystein Lønning, Funda Meric-Bernstam, and Valerie S. LeBleu http://jci.me/90733

Non–small cell lung carcinoma

NF-κB inhibitor–treated muscle

Intratumoral hypoxia

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