jci.org/this-month

Controlling adverse methylation in renal cell carcinoma 3

Compensatory MEK/ERK activation undermines JAK inhibitors 3

Maresin 1/RORα signaling axis ameliorates steatohepatitis 3

Mitochondrial fusion impairments in neurodegenerative disease 4

Review Series: Allergy edited by Kari Nadeau 6

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

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April 2019

miR-30c represses fibrin-mediated tumor angiogenesis p. 2

This Month

Journal of Clinical Investigation Consulting Editors

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j c i . o r g / t h i s - m o n t h a p r i l 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, 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, Paul B. Rothman, Diane E. Griffin, and David Valle

BiostatisticianEliseo Guallar

Computational BiologistPatrick Cahan

JCI ScholarsLaura Cohen, Jared Hinkle

Staff EditorsExecutive EditorSarah C. Jackson

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Editor at LargeUshma S. Neill

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

For the full JCI online: jci.me/129/4

This MonthApril 2019

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

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

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

Timothy H. Moran, PhD, Associ-ate Editor, is the Paul R. McHugh Professor of Motivated Behaviors and Vice Chair and Director of Research in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine. He is also Director of Behavioral and Biological Research in the Johns Hopkins Global Center for Obesity Prevention at the Bloom-berg School of Public Health, where

he has a joint appointment as Professor of International Health. Dr. Moran’s research interests are in brain/behavior relationships as they apply to the con-trol of food intake and body weight, focusing on brain/gut peptides as feed-back controls of meal size, how these interact with neural systems involved in overall energy balance and reward processing, and how these may go awry in eating disorders and obesity.

Publication highlights

Albertz J, Boersma GJ, Tamashiro KL, Moran TH. The effects of scheduled run-ning wheel access on binge-like eating behavior and its consequences. Appetite. 2018;126:176–184.

Chawla A, Cordner ZA, Boersma G, Moran TH. Cognitive impairment and gene expression alterations in a rodent model of binge eating disorder. Physiol Behav. 2017;180:78–90.

Yang Y, Choi PP, Smith WW, Xu W, Ma D, Cordner ZA, Liang NC, Moran TH. Exendin-4 reduces food intake via the PI3K/AKT signaling pathway in the hypothalamus. Sci Rep. 2017;7(1):6936.

Johnson MD, Moran TH. Modulation of receptor signaling by metabolic envi-ronment. Am J Clin Nutr. 2017;106(2):437–438.

(ASCI) indicates corresponding authors who are ASCI members.

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research

Editor’s picks

on the jci cover

miR-30c represses fibrin-mediated tumor angiogenesisThe development of blood vessels that supply oxygen and nutrients to tumors depends on angiogenic signals that cancer cells appropriate from wound healing–like processes. In normal wound healing, fibrin leaks from injured blood vessels to the extravascular space, providing structural support for new vasculature while sequestering TGF-β and other growth factors. Activated plasmin provides a check on fibrin-mediated angiogenesis by degrading fibrin. Certain cancers and endothelial cells express the plasminogen activator inhibitor PAI-1 (encoded by Serpine1) to deregulate this pathway, resulting in a persistent fibrin scaffolding that facilitates tumor angiogenesis and tumor progression. In this issue of the JCI, James McCann et al. report a feed-forward effect of endothelial TGF-β/TGF-βR2 signaling during fibrin-mediated angiogen-esis. In endothelial cells, TGF-βR2 stimulation suppressed miR-30c, which led to increased PAI-1 expression and fibrin deposition. The researchers then demonstrated that a miR-30c mimic delivered via vascular-tropic nanoparticles decreased fibrin deposition, endothelial sprouting, and tumor volume, whereas a miR-30c antagomiR did the opposite. These findings identify endothelial miR-30c as a tumor suppressor within the tumor microenvironment, given its ability to inhibit fibrin-mediated angiogenesis. The cover image shows endothelial cell sprouting in a fibrin matrix. Image credit: James McCann.

Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β–induced Serpine1James V. McCann, Lin Xiao, Dae Joong Kim, Omar F. Khan, Piotr S. Kowalski, Daniel G. Anderson, Chad V. Pecot, Salma H. Azam, Joel S. Parker, Yihsuan S. Tsai, Alisa S. Wolberg, Stephen D. Turner, Kohei Tatsumi, Nigel Mackman, and Andrew C. Dudley http://jci.me/123106

Disrupting Fas signaling broadly enhances adoptive cellular immunotherapies for cancerThe efficacy of adoptive cell transfer (ACT) therapies is limited in part by the durability of transferred T cells within the tumor microenvironment. Tori Yamamoto and colleagues used the TCGA database to screen for factors within human tumor microenvironments that might limit T cell survival. They discovered that the apoptosis-inducing ligand FasL is overexpressed within the majority of tumors evaluated. They designed a series of Fas variants that function as dominant negative receptors (DNRs) to disable Fas signaling in anticancer T cells. Transferred T cells genetically engineered with a Fas DNR displayed enhanced persistence and antitumor efficacy in mouse models of solid and hematologic cancers. Importantly, disrupting Fas signaling did not lead to uncontrolled T cell expansion or autoimmunity. Madhav Dhodapkar’s accompanying Commentary suggests that T cell modification with a Fas DNR may represent a generalizable strategy for improving ACT efficacy across a range of cancer types.

T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapyTori N. Yamamoto, Ping-Hsien Lee, Suman K. Vodnala, Devikala Gurusamy, Rigel J. Kishton, Zhiya Yu, Arash Eidizadeh, Robert Eil, Jessica Fioravanti, Luca Gattinoni, James N. Kochenderfer, Terry J. Fry, Bulent Arman Aksoy, Jeffrey E. Hammerbacher, Anthony C. Cruz, Richard M. Siegel, Nicholas P. Restifo, and Christopher A. Klebanoff http://jci.me/121491

Related CommentaryNavigating the Fas lane to improved cellular therapy for cancerMadhav V. Dhodapkar (ASCI) http://jci.me/127581

oncology

j c i . o r g / t h i s - m o n t h a p r i l 2 0 1 9 3

JCI | Research: Editor’s picks

oncology

hematology

hepatology

Ascorbic acid–enhanced TET curbs cytosine hypermethylation in renal cell carcinomaWidespread cytosine hypermethylation has been reported in clear cell renal cell carcinoma (ccRCC), but its relevance to disease progression and treatment remains unclear. Niraj Shenoy and colleagues analyzed 576 ccRCC patient samples and correlated advanced disease and increased tumor aggressiveness with 5-hydroxymethylcytosine (5hmC) loss, an indicator of reductions in cytosine demethylation. They hypothesized that enhancing the activation of TET enzymes, which mediate the demethylation of 5-methylcytosine to 5hmC, may drive therapeutic epigenetic reprogramming. Indeed, high doses of the TET cofactor ascorbic acid induced loss of methylation and reduced ccRCC growth in vitro and in a xenograft model. These findings suggest that cytosine hypermethylation is a pathogenic mechanism in ccRCC and indicate a potential strategy for mitigating aberrant epigenetic reprogramming.

Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcystosine loss in renal cell carcinomaNiraj Shenoy, Tushar D. Bhagat, John Cheville, Christine Lohse, Sanchari Bhattacharyya, Alexander Tischer, Venkata Machha, Shanisha Gordon-Mitchell, Gaurav Choudhary, Li-Fan Wong, LouAnn Gross, Emily Ressigue, Bradley Leibovich, Stephen A. Boorjian, Ulrich Steidl, Xiaosheng Wu, Kith Pradhan, Benjamin Gartrell, Beamon Agarwal, Lance Pagliaro, Masako Suzuki, John M. Greally, Dinesh Rakheja, R. Houston Thompson, Katalin Susztak, Thomas Witzig, Yiyu Zou, and Amit Verma (ASCI) http://jci.me/98747

MEK targeting boosts JAK inhibitor efficacy against myeloproliferative neoplasmsMyeloproliferative neoplasms (MPNs) comprise a set of chronic leukemias that are characterized by gain-of-function mutations in the JAK2 signaling pathway. At present, only hematopoietic stem cell transplantation can cure these leukemias because MPNs develop resistance to JAK2 inhibitors. Simona Stivala and colleagues determined that, in mouse models, MPNs maintain MEK/ERK overactivation in spite of JAK2 inhibition. Mechanistically, they found that PGFR-BB/PDGFRα signaling circumvented JAK2 inhibition, eliciting JAK2-independent MEK/ERK activity. In mouse models of MPN, simultaneous JAK2/MEK inhibition enhanced therapeutic efficacy and reduced hypercellularity relative to either treatment alone (see the associated image). In the accompanying Commentary, David Williams unpacks the evidence that targeting compensatory MEK/ERK activation may improve responses to JAK inhibitors in JAK-mutant malignancies.

Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasmsSimona Stivala, Tamara Codilupi, Sime Brkic, Anne Baerenwaldt, Nilabh Ghosh, Hui Hao-Shen, Stephan Dirnhofer, Matthias S. Dettmer, Cedric Simillion, Beat A. Kaufmann, Sophia Chiu, Matthew Keller, Maria Kleppe, Morgane Hilpert, Andreas S. Buser, Jakob R. Passweg, Thomas Radimerski, Radek C. Skoda, Ross L. Levine (ASCI), and Sara C. Meyer http://jci.me/98785

Related CommentaryPairing JAK with MEK for improved therapeutic efficiency in myeloproliferative disordersDavid A. Williams (ASCI) http://jci.me/127582

Maresin 1 and RORα interactions protect against diet-induced liver inflammationThe chronic liver inflammation that character-izes nonalcoholic steatohepatitis (NASH) is mediated by liver macrophages, whose functions tend toward either proinflammatory (M1) or anti-inflammatory (M2). The orphan receptor RORα may influence NASH pathogenesis by regulating shifts in M1 versus M2 polarity. Yong-Hyun Han and colleagues identified the lipid mediator maresin 1 (MaR1) as an endogenous RORα ligand that enhances M2 polarization in liver macro-phages. Systemic MaR1 administration prevented the development of NASH-like inflammation in mice fed a high-fat diet, an effect that required RORα expression and corresponded to increases in M2-like macrophages. RORα itself appeared to control MaR1 synthesis by regulating the expression of 12-LOX, a key synthetic enzyme that converts the dietary omega-3 fatty acid DHA to MaR1. Matthew Spite describes the potential to exploit the MaR1/RORα/12-LOX circuit’s protective effects against NASH in an accompa-nying Commentary.

A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitisYong-Hyun Han, Kyong-Oh Shin, Ju-Yeon Kim, Daulat B. Khadka, Hyeon-Ji Kim, Yong-Moon Lee, Won-Jea Cho, Ji-Young Cha, Bong-Jin Lee, and Mi-Ock Lee http://jci.me/124219

Related CommentaryResolving inflammation in nonalcoholic steatohepatitisMatthew Spite http://jci.me/127583

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JCI | Research: Editor’s picks

neuroscience

Increasing MFN1 restores mitochondrial fusion in a Charcot-Marie-Tooth type 2A model

NOX5-dependent ROS production disrupts blood-brain barrier integrity following ischemic strokeRecovery from ischemic stroke is complicated by calcium-dependent oxidative damage to the blood-brain barrier (BBB) that occurs during reperfusion of brain tissue. Ana I. Casas, Pamela Kleikers, and colleagues identified the calcium-activated NADPH oxidase NOX5 as an important contributor to excessive ROS production and went on to examine its potential as a therapeutic target. In models of stroke, BBB disruption and infarct volume were substantially greater in mice expressing the human NOX5 gene compared with WT counterparts (see the associated image). The effect was brain specific, as NOX5 expression did not alter ROS formation or postischemic outcomes in models of myocardial

infarction, hindlimb ischemia, or cardiac ischemia-reperfusion injury. Pharmacological NOX5 inhibition prevented increases in human brain microvascular endothelial cell permeability following hypoxia and reoxygenation, suggesting that targeting NOX5 in the aftermath of stroke may help preserve BBB integrity. Luciana Carmo, Bradford Berk, and David Harrison call for further investigation of NOX5 inhibition in humans in an accompanying Commentary.

Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in strokeAna I. Casas, Pamela W.M. Kleikers, Eva Geuss, Friederike Langhauser, Thure Adler, Dirk H. Busch, Valerie Gailus-Durner, Martin Hrabê de Angelis, Javier Egea, Manuela G. Lopez, Christoph Kleinschnitz, and Harald H.H.W. Schmidt http://jci.me/124283

Related CommentaryNOX5 as a therapeutic target in cerebral ischemic injuryLuciana Simão do Carmo, Bradford C. Berk, and David G. Harrison (ASCI) http://jci.me/127682

The neurological disorder Charcot-Marie-Tooth disease type 2A (CMT2A) is attributed to mutations in MFN2, which encodes a mitochondrial GTPase that regulates mitochondrial fusion and other functions. Yueqin Zhou and colleagues developed a mouse model of CMT2A that recapitulates the severe sensorimotor deficits and mitochondrial dysfunction that typify the disease. As human MFN2 mutations predominantly affect the nervous system, the CMT2A mice were developed to express the human point mutation under the control of a neuron-specific promoter. In CMT2A mice, mutant MFN2 induced axon degeneration and mitochondrial clustering due to incompetent mitochondrial fusion. Enhancing expression of MFN1, which is normally expressed at low levels in neurons, rescued these neuronal and mitochondrial defects (see the associated image). In the accompanying Commentary, Keiko Iwata and Luca Scorrano discuss the possibility that increasing MFN1 expression in the nervous system may benefit CMT2A patients.

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A modelYueqin Zhou, Sharon Carmona, A.K.M.G. Muhammad, Shaughn Bell, Jesse Landeros, Michael Vazquez, Ritchie Ho, Antonietta Franco, Bin Lu, Gerald W. Dorn II, Shaomei Wang, Cathleen M. Lutz, and Robert H. Baloh (ASCI) http://jci.me/124194

Related CommentaryFinding a new balance to cure Charcot-Marie-Tooth 2AKeiko Iwata and Luca Scorrano http://jci.me/127820

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JCI | Research: Editor’s picks

neuroscience

news

Sepsis-induced heparan sulfate fragments impair memory and synaptic plasticityPersistent cognitive impairment after sepsis is both common and debilitating. This phenomenon has previously been associated with blood-brain barrier disruption and reduced volume of the hippocampus, a brain structure central to learning and memory. Joseph Hippensteel and colleagues investigated the mechanisms underlying sepsis-induced cognitive dysfunction, focusing on the growth factor brain-derived neurotrophic factor (BDNF), a critical regulator of hippocampal synaptic plasticity. In mice, LPS-induced endotoxemia impaired memory and synaptic plasticity without altering hippocampal BDNF content. They hypothesized that circulating heparan sulfate fragments shed from the endothelium during sepsis may act as inhibitors of BDNF signaling. Heparan sulfate fragments were present in the hippocampus of endotoxemic mice and were capable of inhibiting BDNF-induced synaptic plasticity. In septic patients, elevated circulating heparan sulfate correlated with persistent cognitive impairment. In an accompanying Commentary, Benjamin Singer highlights heparan sulfate’s inhibition of BDNF as a potentially targetable mechanism that opens a new pathway for intervention in sepsis survivors.

Circulating heparan sulfate fragments mediate septic cognitive dysfunctionJoseph A. Hippensteel, Brian J. Anderson, James E. Orfila, Sarah A. McMurtry, Robert M. Dietz, Guowei Su, Joshay A. Ford, Kaori Oshima, Yimu Yang, Fuming Zhang, Xiaorui Han, Yanlei Yu, Jian Liu, Robert J. Linhardt, Nuala J. Meyer, Paco S. Herson, and Eric P. Schmidt http://jci.me/124485

Related CommentaryThe vasculature in sepsis: delivering poison or remedy to the brain?Benjamin H. Singer http://jci.me/127679

The JCI interviews 2019 Korsmeyer award–winner Michael S. DiamondThis year, the ASCI recognizes Michael S. Diamond of Washington University School of Medicine with the Stanley J. Korsmeyer award for his work elucidating the pathogenesis of emerging RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Dr. Diamond’s recent accomplishments include the development of a mouse model of Zika infection that helped accelerate research and responses during the initial outbreak. In an interview with the JCI, he discusses the early interests in global health and science that influenced his decision to specialize in infectious disease. He also describes strategies that may help the scientific and medical communities rapidly address future outbreaks of viral diseases.

Infectious disease expert Michael S. Diamond wins the 2019 ASCI/Stanley J. Korsmeyer prizeSarah Jackson http://jci.me/128050

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JCI | Review Series

Nothing to sneeze at: insights into allergy treatment and prevention

JCI Review Series

allergySeries Editor: Kari Nadeau

The increasing prevalence of allergies worldwide has spurred numerous efforts to better understand risk factors and mechanisms underlying these potentially life- threatening immune responses. Coordinated by Series Editor Kari Nadeau, these reviews address our evolving understanding of the shared and distinct mechanisms underlying allergic diseases of the skin, respiratory system, and gastrointestinal tract. In topics ranging from the molecular and cellular basis of allergy to the influence of the central nervous system, microbiome, and environment, leaders in the field highlight major insights into allergic responses, as well as new concepts in treating and preventing allergies. The highlighted figure from Hiroki Kabata and David Artis’s review illustrates the contribution of neuroimmune interactions to the allergic response.

Mechanisms of gastrointestinal allergic disordersNurit P. Azouz and Marc E. Rothenberg (ASCI) http://jci.me/124604

Newly identified T cell subsets in mechanistic studies of food immunotherapyVanitha Sampath and Kari C. Nadeau (ASCI) http://jci.me/124605

Epithelial cell–derived cytokines: more than just signaling the alarmFlorence Roan, Kazushige Obata-Ninomiya, and Steven F. Ziegler http://jci.me/124606

The use of biologics for immune modulation in allergic diseaseWillem van de Veen and Mübeccel Akdis http://jci.me/124607

Epithelial barrier repair and prevention of allergyElena Goleva, Evgeny Berdyshev, and Donald Y.M. Leung (ASCI) http://jci.me/124608

Neuro-immune crosstalk and allergic inflammationHiroki Kabata and David Artis http://jci.me/124609

Influences on allergic mechanisms through gut, lung, and skin microbiome exposuresAndrea M. Kemter and Cathryn R. Nagler http://jci.me/124610

Precision medicine and phenotypes, endotypes, genotypes, regiotypes, and theratypes of allergic diseasesIoana Agache and Cezmi A. Akdis http://jci.me/124611

Environmental exposures and mechanisms in allergy and asthma developmentLiza Bronner Murrison, Eric B. Brandt, Jocelyn Biagini Myers, and Gurjit K. Khurana Hershey (ASCI) http://jci.me/124612

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Current research articles

clinical medicineBone marrow stromal cells from β-thalassemia patients have impaired hematopoietic supportive capacityStefania Crippa, Valeria Rossella, Annamaria Aprile, Laura Silvestri, Silvia Rivis, Samantha Scaramuzza, Stefania Pirroni, Maria Antonietta Avanzini, Luca Basso-Ricci, Raisa Jofra Hernandez, Marco Zecca, Sarah Marktel, Fabio Ciceri, Alessandro Aiuti, Giuliana Ferrari, and Maria Ester Bernardo http://jci.me/123191

hematologyTargeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms p. 3Simona Stivala, Tamara Codilupi, Sime Brkic, Anne Baerenwaldt, Nilabh Ghosh, Hui Hao-Shen, Stephan Dirnhofer, Matthias S. Dettmer, Cedric Simillion, Beat A. Kaufmann, Sophia Chiu, Matthew Keller, Maria Kleppe, Morgane Hilpert, Andreas S. Buser, Jakob R. Passweg, Thomas Radimerski, Radek C. Skoda, Ross L. Levine (ASCI), and Sara C. Meyer http://jci.me/98785

hepatologyA maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis p. 3Yong-Hyun Han, Kyong-Oh Shin, Ju-Yeon Kim, Daulat B. Khadka, Hyeon-Ji Kim, Yong-Moon Lee, Won-Jea Cho, Ji-Young Cha, Bong-Jin Lee, and Mi-Ock Lee http://jci.me/124219

infectious diseaseDengue-specific CD8+ T cell subsets display specialized transcriptomic and TCR profilesYuan Tian, Mariana Babor, Jerome Lane, Grégory Seumois, Shu Liang, N.D. Suraj Goonawardhana, Aruna D. De Silva, Elizabeth J. Phillips, Simon A. Mallal, Ricardo da Silva Antunes, Alba Grifoni, Pandurangan Vijayanand, Daniela Weiskopf, Bjoern Peters, and Alessandro Sette http://jci.me/123726

nephrologyNonimmune cell–derived ICOS ligand functions as a renoprotective αvβ3 integrin–selective antagonistKwi Hye Koh, Yanxia Cao, Steve Mangos, Nicholas J. Tardi, Ranadheer R. Dande, Ha Won Lee, Beata Samelko, Mehmet M. Altintas, Vincent P. Schmitz, Hyun Lee, Kamalika Mukherjee, Vasil Peev, David J. Cimbaluk, Jochen Reiser, and Eunsil Hahm http://jci.me/123386

neuroscienceAbolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in miceMaría Isabel Cuartero, Juan de la Parra, Alberto Pérez-Ruiz, Isabel Bravo-Ferrer, Violeta Durán-Laforet, Alicia García-Culebras, Juan Manuel García-Segura, Jagroop Dhaliwal, Paul W. Frankland, Ignacio Lizasoain, and María Ángeles Moro http://jci.me/120412

Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathologySilvia Pozzi, Sai Sampath Thammisetty, Philippe Codron, Reza Rahimian, Karine Valérie Plourde, Geneviève Soucy, Christine Bareil, Daniel Phaneuf, Jasna Kriz, Claude Gravel, and Jean-Pierre Julien http://jci.me/123931

Healthy donor bone marrow cells

ICOS ligand in human podocytes

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Current research articles

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model p. 4Yueqin Zhou, Sharon Carmona, A.K.M.G. Muhammad, Shaughn Bell, Jesse Landeros, Michael Vazquez, Ritchie Ho, Antonietta Franco, Bin Lu, Gerald W. Dorn II, Shaomei Wang, Cathleen M. Lutz, and Robert H. Baloh (ASCI) http://jci.me/124194

Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke p. 4Ana I. Casas, Pamela W.M. Kleikers, Eva Geuss, Friederike Langhauser, Thure Adler, Dirk H. Busch, Valerie Gailus-Durner, Martin Hrabê de Angelis, Javier Egea, Manuela G. Lopez, Christoph Kleinschnitz, and Harald H.H.W. Schmidt http://jci.me/124283

Circulating heparan sulfate fragments mediate septic cognitive dysfunction p. 5Joseph A. Hippensteel, Brian J. Anderson, James E. Orfila, Sarah A. McMurtry, Robert M. Dietz, Guowei Su, Joshay A. Ford, Kaori Oshima, Yimu Yang, Fuming Zhang, Xiaorui Han, Yanlei Yu, Jian Liu, Robert J. Linhardt, Nuala J. Meyer, Paco S. Herson, and Eric P. Schmidt http://jci.me/124485

oncologyT cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy p. 2Tori N. Yamamoto, Ping-Hsien Lee, Suman K. Vodnala, Devikala Gurusamy, Rigel J. Kishton, Zhiya Yu, Arash Eidizadeh, Robert Eil, Jessica Fioravanti, Luca Gattinoni, James N. Kochenderfer, Terry J. Fry, Bulent Arman Aksoy, Jeffrey E. Hammerbacher, Anthony C. Cruz, Richard M. Siegel, Nicholas P. Restifo, and Christopher A. Klebanoff http://jci.me/121491

RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growthShaikamjad Umesalma, Courtney A. Kaemmer, Jordan L. Kohlmeyer, Blake Letney, Angela M. Schab, Jacqueline A. Reilly, Ryan M. Sheehy, Jussara Hagen, Nitija Tiwari, Fenghuang Zhan, Mariah R. Leidinger, Thomas M. O’Dorisio, Joseph Dillon, Ronald A. Merrill, David K. Meyerholz, Abbey L. Perl, Bart J. Brown, Terry A. Braun, Aaron T. Scott, Timothy Ginader, Agshin F. Taghiyev, Gideon K. Zamba, James R. Howe, Stefan Strack, Andrew M. Bellizzi, Goutham Narla, Benjamin W. Darbro, Frederick W. Quelle, and Dawn E. Quelle http://jci.me/123049

Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β–induced Serpine1 p. 2James V. McCann, Lin Xiao, Dae Joong Kim, Omar F. Khan, Piotr S. Kowalski, Daniel G. Anderson, Chad V. Pecot, Salma H. Azam, Joel S. Parker, Yihsuan S. Tsai, Alisa S. Wolberg, Stephen D. Turner, Kohei Tatsumi, Nigel Mackman, and Andrew C. Dudley http://jci.me/123106

IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinomaAlex B. Blair, Jennifer Kleponis, Dwayne L. Thomas II, Stephen T. Muth, Adrian G. Murphy, Victoria Kim, and Lei Zheng http://jci.me/124077

Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenicSarah Tomkovich, Christine M. Dejea, Kathryn Winglee, Julia L. Drewes, Liam Chung, Franck Housseau, Jillian L. Pope, Josee Gauthier, Xiaolun Sun, Marcus Mühlbauer, Xiuli Liu, Payam Fathi, Robert A. Anders, Sepideh Besharati, Ernesto Perez-Chanona, Ye Yang, Hua Ding, Xinqun Wu, Shaoguang Wu, James R. White, Raad Z. Gharaibeh, Anthony A. Fodor, Hao Wang, Drew M. Pardoll, Christian Jobin, and Cynthia L. Sears (ASCI) http://jci.me/124196

Gliosis in CMT2A mouse brainstem

Neuroendocrine tumor cells

j c i . o r g / t h i s - m o n t h a p r i l 2 0 1 9 9

Flip issue to read JCI Insight content.

Spatially distinct tumor immune microenvironments stratify triple-negative breast cancersTina Gruosso, Mathieu Gigoux, Venkata Satya Kumar Manem, Nicholas Bertos, Dongmei Zuo, Irina Perlitch, Sadiq Mehdi Ismail Saleh, Hong Zhao, Margarita Souleimanova, Radia Marie Johnson, Anne Monette, Valentina Muñoz Ramos, Michael Trevor Hallett, John Stagg, Réjean Lapointe, Atilla Omeroglu, Sarkis Meterissian, Laurence Buisseret, Gert Van den Eyden, Roberto Salgado, Marie-Christine Guiot, Benjamin Haibe-Kains, and Morag Park http://jci.me/96313

Follicular lymphoma–associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and mTORFangyang Wang, Damián Gatica, Zhang Xiao Ying, Luke F. Peterson, Peter Kim, Denzil Bernard, Kamlai Saiya-Cork, Shaomeng Wang, Mark S. Kaminski, Alfred E. Chang, Tycel Phillips, Daniel J. Klionsky, and Sami N. Malek (ASCI) http://jci.me/98288

Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma p. 3Niraj Shenoy, Tushar D. Bhagat, John Cheville, Christine Lohse, Sanchari Bhattacharyya, Alexander Tischer, Venkata Machha, Shanisha Gordon-Mitchell, Gaurav Choudhary, Li-Fan Wong, LouAnn Gross, Emily Ressigue, Bradley Leibovich, Stephen A. Boorjian, Ulrich Steidl, Xiaosheng Wu, Kith Pradhan, Benjamin Gartrell, Beamon Agarwal, Lance Pagliaro, Masako Suzuki, John M. Greally, Dinesh Rakheja, R. Houston Thompson, Katalin Susztak, Thomas Witzig, Yiyu Zou, and Amit Verma (ASCI) http://jci.me/98747

virologyCytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesisHarald Krenzlin, Prajna Behera, Viola Lorenz, Carmela Passaro, Mykola Zdioruk, Michal O. Nowicki, Korneel Grauwet, Hong Zhang, Magdalena Skubal, Hirotaka Ito, Rachel Zane, Michael Gutknecht, Marion B. Griessl, Franz Ricklefs, Lai Ding, Sharon Peled, Arun Rooj, C. David James, Charles S. Cobbs, Charles H. Cook, E. Antonio Chiocca, and Sean E. Lawler http://jci.me/123375

Breast tumor immune infiltrate

Murine glioblastoma tumor

jci.org/this-month

Sex-specific immune cell differences determine EAE manifestation 11

Tofacitinib improves delivery of antibody-based drugs to target tumor cells 12

Cannabinoid type-1 receptors control exercise motivation 12

CD274 identified as a potential therapeutic target for IPF 13

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

April 2019

B cell hyperplasia inimmunodeficiency-associated lung disease p. 10

This Month

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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

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

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

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

Michail S. Lionakis

Carey N. Lumeng

Ivan Maillard

Ziad Mallat

Peter Mannon

Franck Mauvais-Jarvis

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

David K. Meyerholz

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

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

Fumihiko Urano

Deborah J. Veis

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

j c i . o r g / t h i s - m o n t h a p r i l 2 0 1 9 10

For JCI InsightEditorHoward A. RockmanAssociate EditorsVann Bennett, Rodger A. Liddle, Yiping YangExecutive EditorSarah C. JacksonScience EditorCorinne Williams

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On the JCI Insight cover

This MonthApril 2019

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BAFF-driven B cell hyperplasia promotes common variable immunodeficiency– associated lung disease

Interstitial lung disease (ILD) is a life-threatening complication that devel-ops in a subset of patients with common variable immunodeficiency (CVID). ILD can be stable or progressive; however, the factors that drive progression are poorly understood, and there is a paucity of treatments available to slow this disease. In this issue, PJ Maglione and colleagues examined a cohort of 73 CVID patients to investigate links between clinical parameters and the development of ILD. In these patients, ILD progression associated with increased levels of serum IgM, which was reflective of increased B cell hyperplasia and follicle formation in the lungs. B cell–activating factor (BAFF) was increased in both the lungs and blood of patients with progressive disease. Treatment of patients with the B cell–depleting antibody rituximab ameliorated CVID-associated ILD. However, ILD relapse occurred in a subset of rituximab-treated patients and associated with increased BAFF. BAFF was shown to promote disease through induction of Bcl-2 in naive B cells, thereby inhibiting apoptosis. These results identify BAFF-driven B cell hyperplasia in the lungs as a driver of CVID-associated ILD. The cover image shows extensive IgM (green) and IgD (red) staining in a lung biopsy from a CVID patient with ILD and high levels of serum IgM.

BAFF-driven B cell hyperplasia underlies lung disease in common variable immunodeficiencyPaul J. Maglione, Gavin Gyimesi, Montserrat Cols, Lin Radigan, Huaibin M. Ko, Tamar Weinberger, Brian H. Lee, Emilie K. Grasset, Adeeb H. Rahman, Andrea Cerutti, and Charlotte Cunningham-Rundles http://jci.me/122728

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Editor’s picks

immunology

autoimmunitydermatology

Clonal B cell populations persist in multiple sclerosis patients’ cerebrospinal fluid

Sex-specific immune cell differences determine autoimmune encephalomyelitis presentationMultiple sclerosis has a complex etiology with sex-specific differences in clinical presentation that are not completely understood. Tessa Dhaeze and colleagues used the TCR1640 mouse model of experimental autoimmune encephalomyelitis (EAE), which recapitulates sex-specific differences — including higher incidence of relapsing-remitting disease in females compared with progressive disease in males — to evaluate the contribution of immune cells to disease development. Immune cells from male TCR1640 mice produced progressive disease, while immune cells from female TCR1640 mice manifested relapsing-remitting disease in WT mice, regardless of the sex of the recipient. Genetic profiling of donor immune cells revealed sex-specific differences in transcriptomic profiles, especially in genes related to T cell immunity. The results of this study indicate that sex-specific differences in immune cells underlie EAE manifestation.

Sex-dependent factors encoded in the immune compartment dictate relapsing or progressive phenotype in demyelinating diseaseTessa Dhaeze, Catherine Lachance, Laurence Tremblay, Camille Grasmuck, Lyne Bourbonnière, Sandra Larouche, Olivia Saint-Laurent, Marc-André Lécuyer, Rose-Marie Rébillard, Stephanie Zandee, and Alexandre Prat http://jci.me/124885

Combination treatment for actinic keratosis reduces squamous cell carcinoma incidenceActinic keratosis (AK) resulting from UV skin damage is a common precursor to cutaneous squamous cell carcinoma (SCC). Topical administration of calcipotriol plus 5-fluorouracil (5-FU) immunotherapy can eliminate AK; however, it is unclear whether this combination is effective for long-term prevention of SCC. Following a randomized trial of a 4-day course of calcipotriol plus 5-FU (combination) or Vaseline plus 5-FU (control) in patients with AK, Abby Rosenberg and colleagues performed a double-blinded prospective cohort analysis assessing SCC incidence at 1, 2, and 3 years after treatment. Compared with control-treated subjects, those who received combination treatment developed fewer SCCs on the treated face and scalp. Moreover, combination treatment associated with the induction of tissue-resident memory T cells (see the accompanying image) in the treated skin. The results support further evaluation of calcipotriol plus 5-FU for preventing SCC in patients with AK.

Skin cancer precursor immunotherapy for squamous cell carcinoma preventionAbby R. Rosenberg, Mary Tabacchi, Kenneth H. Ngo, Michael Wallendorf, Ilana S. Rosman, Lynn A. Cornelius, and Shadmehr Demehri http://jci.me/125476

Multiple sclerosis (MS) is an autoimmune disease driven in part by dysfunctional B cell responses. B cells are found in the cerebrospinal fluid (CSF) of MS patients, but their clonal persistence over time and relationship to disease and treatment response have not been fully explored. Ariele Greenfield and colleagues collected CSF and peripheral blood from a small cohort of 10 untreated MS patients, and again from the same patients at a later time point, when 7 patients were now treated with typical MS therapies. Clonally persistent B cells were detected in the CSF of 5 patients, even in those who had started high-efficacy immunomodulatory therapy. These findings suggest that some potentially disease-relevant immunological mechanisms of MS involving B cells may resist treatment.

Longitudinally persistent cerebrospinal fluid B cells can resist treatment in multiple sclerosisAriele L. Greenfield, Ravi Dandekar, Akshaya Ramesh, Erica L. Eggers, Hao Wu, Sarah Laurent, William Harkin, Natalie S. Pierson, Martin S. Weber, Roland G. Henry, Antje Bischof, Bruce A.C. Cree, Stephen L. Hauser, Michael R. Wilson, and H.-Christian von Büdingen http://jci.me/126599

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JCI Insight | Editor’s picks

12

oncology

neuroscience

Pan-JAK inhibitor improves tumor targeting of antibody-based therapeuticsThe success of antibody-based therapies to target tumor-associated antigens is dependent on delivery of these agents to the target cell. There are several challenges, including immune-mediated interference, that limit efficient delivery and effective antitumor responses. As previous studies have shown that the pan-JAK inhibitor tofacitinib reduces antidrug immune responses, Nathan Simon and colleagues from the National Institutes of Health investigated the effects of tofacitinib on antitumor responses in murine models of breast and pancreatic cancer. Tofacitinib alone had no antitumor activity but dramatically increased accumulation of antibody-based agents in malignant cells. The tofacitinib-associated increase in tumor targeting corresponded with changes in the tumor microenvironment, including decreased cytokine expression and a reduction in tumor-associated inflammatory cells (see the accompanying image), which contribute to non-target uptake of antibody-based drugs. These results provide support for the use of tofacitinib to improve tumor cell targeting of antibody-based drugs.

Tofacitinib enhances delivery of antibody-based therapeutics to tumor cells through modulation of inflammatory cellsNathan Simon, Antonella Antignani, Stephen M. Hewitt, Massimo Gadina, Christine Alewine, and David FitzGerald http://jci.me/123281

Cannabinoid type-1 receptor signaling gets mice motivated to exerciseLack of motivation to routinely engage in physical activity is a major challenge for reducing global obesity levels. The neurological pathways that influence exercise motivation are poorly understood and could provide targets for modifying behavior. Using operant conditioning, Carolina Muguruza, Bastien Redon, and colleagues developed a murine model that specifically allows evaluation of exercise motivation and investigated the involvement of the endocannabinoid system in this process. Mice treated with cannabinoid type-1 receptor (CB1R) antagonists or deficient for CB1R exhibited a lack of intrinsic exercise motivation. CB1R signaling in GABAergic neurons was found to be necessary and sufficient for exercise motivation. As a consequence, lack of CB1R in GABAergic neurons promoted a preference for palatable food over running when mice were presented that choice. Together, these results provide a model to investigate exercise motivation and link dysfunctional CB1R signaling to sedentarity.

The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptorsCarolina Muguruza, Bastien Redon, Giulia R. Fois, Imane Hurel, Amandine Scocard, Claire Nguyen, Christopher Stevens, Edgar Soria-Gomez, Marjorie Varilh, Astrid Cannich, Justine Daniault, Arnau Busquets-Garcia, Teresa Pelliccia, Stéphanie Caillé, François Georges, Giovanni Marsicano, and Francis Chaouloff http://jci.me/126190

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j c i . o r g / t h i s - m o n t h a p r i l 2 0 1 913

JCI Insight | Editor’s picks

pulmonology

ACE inhibitors may delay lymphangioleiomyomatosis-associated lung function declineLymphangioleiomyomatosis is a rare disease that primarily affects women and is characterized by aberrant proliferation of smooth muscle–like cells throughout the lungs, resulting in loss of pulmonary function. Sirolimus stabilizes lung function in many patients with lymphangioleiomyomatosis; however, not all patients respond to or tolerate this therapeutic approach. Previous work has shown the presence of a local renin-angiotensin system in lymphangioleiomyomatosis nodules; therefore, Wendy Steagall and colleagues retrospectively evaluated angiotensin-converting enzyme (ACE) levels, pulmonary function, and ACE inhibitor use in 426 patients with lymphangioleiomyomatosis. ACE levels were elevated in a subset of patients and corresponded with decreased lung function. Sirolimus reduced ACE levels, and ACE inhibitor usage was linked to a slower rate of lung function decline. These results suggest that ACE inhibitors should be further explored for lymphangioleiomyomatosis treatment.

Angiotensin-converting enzyme inhibitors may affect pulmonary function in lymphangioleiomyomatosisWendy K. Steagall, Mario Stylianou, Gustavo Pacheco-Rodriguez, and Joel Moss http://jci.me/126703

PD-L1 on IPF-derived fibroblasts determines invasive phenotype and disease severity

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Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of lung function due to excessive deposition of extracellular matrix. Compared with normal pulmonary fibroblasts, IPF patient fibroblasts have an invasive phenotype that is linked to disease severity. Yan Geng and colleagues performed RNA sequencing to compare gene expression profiles of noninvasive and invasive fibroblasts derived from IPF patients. The immune checkpoint ligand PD-L1 (also known as CD274) was upregulated and required for the invasive phenotype. In a humanized mouse IPF model, PD-L1–expressing, patient-derived fibroblasts and fibroblasts with induced PD-L1 expression promoted severe pulmonary fibrosis. Moreover, both genetic and antibody targeting of PD-L1 in IPF fibroblasts attenuated lung fibrosis development in humanized mice (see the accompanying image). Cumulatively, these results identify PD-L1 as a driver of IPF fibroblast invasion and support PD-L1 as a potential therapeutic target for IPF.

PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosisYan Geng, Xue Liu, Jiurong Liang, David Habiel, Kulur Vrishika, Ana Lucia Coelho, Nan Deng, Ting Xie, Yizhou Wang, Ningshan Liu, Guanling Huang, Adrianne Kurkciyan, Zhenqiu Liu, Jie Tang, Cory Hogaboam, Dianhua Jiang, and Paul W. Noble (ASCI) http://jci.me/125326

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Current articles

PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophyShigeki Nishimori, Forest Lai, Mieno Shiraishi, Tatsuya Kobayashi, Elena Kozhemyakina, Tso-Pang Yao, Andrew B. Lassar, and Henry M. Kronenberg (ASCI) http://jci.me/97903

Intestinal clock system regulates skeletal homeostasisMasanobu Kawai, Saori Kinoshita, Miwa Yamazaki, Keiko Yamamoto, Clifford J. Rosen, Shigeki Shimba, Keiichi Ozono, and Toshimi Michigami http://jci.me/121798

The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine–induced ER stress responseYuanming Xu, Johanna Melo-Cardenas, Yana Zhang, Isabella Gau, Juncheng Wei, Elena Montauti, Yusi Zhang, Beixue Gao, Hongjian Jin, Zhaolin Sun, Sang-Myeong Lee, and Deyu Fang http://jci.me/121887

Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host diseaseJinfeng Yang, Abdulraouf Ramadan, Dawn K. Reichenbach, Michael Loschi, Jilu Zhang, Brad Griesenauer, Hong Liu, Keli L. Hippen, Bruce R. Blazar, and Sophie Paczesny (ASCI) http://jci.me/122014

TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neuronsRunping Wang, Yongjun Lu, Michael Z. Cicha, Madhu V. Singh, Christopher J. Benson, Christopher J. Madden, Mark W. Chapleau, and François M. Abboud (ASCI) http://jci.me/122058

Mature neutrophils suppress T cell immunity in ovarian cancer microenvironmentKelly L. Singel, Tiffany R. Emmons, ANM Nazmul H. Khan, Paul C. Mayor, Shichen Shen, Jerry T. Wong, Kayla Morrell, Kevin H. Eng, Jaron Mark, Richard B. Bankert, Junko Matsuzaki, Richard C. Koya, Anna M. Blom, Kenneth R. McLeish, Jun Qu, Sanjay Ram, Kirsten B. Moysich, Scott I. Abrams, Kunle Odunsi, Emese Zsiros, and Brahm H. Segal http://jci.me/122311

Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammationXiuxia Zhou, Carol L. Kinlough, Rebecca P. Hughey, Mingzhu Jin, Hideki Inoue, Emily Etling, Brian D. Modena, Naftali Kaminski, Eugene R. Bleecker, Deborah A. Meyers, Nizar N. Jarjour, John B. Trudeau, Fernando Holguin, Anuradha Ray, and Sally E. Wenzel http://jci.me/122475

BAFF-driven B cell hyperplasia underlies lung disease in common variable immunodeficiency p. 10Paul J. Maglione, Gavin Gyimesi, Montserrat Cols, Lin Radigan, Huaibin M. Ko, Tamar Weinberger, Brian H. Lee, Emilie K. Grasset, Adeeb H. Rahman, Andrea Cerutti, and Charlotte Cunningham-Rundles http://jci.me/122728

Platelet-derived β2M regulates monocyte inflammatory responsesZachary T. Hilt, Daphne N. Pariser, Sara K. Ture, Amy Mohan, Pearl Quijada, Akua A. Asante, Scott J. Cameron, Julie A. Sterling, Alyssa R. Merkel, Andrew L. Johanson, Jermaine L. Jenkins, Eric M. Small, Kathleen E. McGrath, James Palis, Michael R. Elliott, and Craig N. Morrell http://jci.me/122943

SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanismsSoravis Osataphan, Chiara Macchi, Garima Singhal, Jeremy Chimene-Weiss, Vicencia Sales, Chisayo Kozuka, Jonathan M. Dreyfuss, Hui Pan, Yanin Tangcharoenpaisan, Jordan Morningstar, Robert Gerszten, and Mary-Elizabeth Patti (ASCI) http://jci.me/123130

Tofacitinib enhances delivery of antibody-based therapeutics to tumor cells through modulation of inflammatory cells p. 12Nathan Simon, Antonella Antignani, Stephen M. Hewitt, Massimo Gadina, Christine Alewine, and David FitzGerald http://jci.me/123281

Ets1 suppresses atopic dermatitis by suppressing pathogenic T cell responsesChoong-Gu Lee, Ho-Keun Kwon, Hyeji Kang, Young Kim, Jong Hee Nam, Young Ho Won, Sunhee Park, Taemook Kim, Keunsoo Kang, Dipayan Rudra, Chang-Duk Jun, Zee Yong Park, and Sin-Hyeog Im http://jci.me/124202

KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivityHui Sun, An-Hsuan Lin, Fei Ru, Mayur J. Patil, Sonya Meeker, Lu-Yuan Lee, and Bradley J. Undem http://jci.me/124467

Propionibacterium acnes–induced immunopathology correlates with health and disease associationStacey L. Kolar, Chih-Ming Tsai, Juan Torres, Xuemo Fan, Huiying Li, and George Y. Liu (ASCI) http://jci.me/124687

Changes in body composition and weight during the menopause transitionGail A. Greendale, Barbara Sternfeld, MeiHua Huang, Weijuan Han, Carrie Karvonen-Gutierrez, Kristine Ruppert, Jane A. Cauley, Joel S. Finkelstein, Sheng-Fang Jiang, and Arun S. Karlamangla http://jci.me/124865

Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanomaYana G. Najjar, Ashley V. Menk, Cindy Sander, Uma Rao, Arivarasan Karunamurthy, Roma Bhatia, Shuyan Zhai, John M. Kirkwood, and Greg M. Delgoffe http://jci.me/124989

Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenanceDongwon Choi, Eunkyung Park, Eunson Jung, Boksik Cha, Somin Lee, James Yu, Paul M. Kim, Sunju Lee, Yeo Jin Hong, Chester J. Koh, Chang-Won Cho, Yifan Wu, Noo Li Jeon, Alex K. Wong, Laura Shin, S. Ram Kumar, Ivan Bermejo-Moreno, R. Sathish Srinivasan, Il-Taeg Cho, and Young-Kwon Hong http://jci.me/125068

Improved efficacy of a next-generation ERT in murine Pompe diseaseSu Xu, Yi Lun, Michelle Frascella, Anadina Garcia, Rebecca Soska, Anju Nair, Abdul S. Ponery, Adriane Schilling, Jessie Feng, Steven Tuske, Maria Cecilia Della Valle, José A. Martina, Evelyn Ralston, Russell Gotschall, Kenneth J. Valenzano, Rosa Puertollano, Hung V. Do, Nina Raben, and Richie Khanna http://jci.me/125358

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Current articles

Multiparametric liquid biopsy analysis in metastatic prostate cancerEmmanuelle Hodara, Gareth Morrison, Alexander Cunha, Daniel Zainfeld, Tong Xu, Yucheng Xu, Paul W. Dempsey, Paul C. Pagano, Farideh Bischoff, Aditi Khurana, Samuel Koo, Marc Ting, Philip D. Cotter, Mathew W. Moore, Shelly Gunn, Joshua Usher, Shahrooz Rabizadeh, Peter Danenberg, Kathleen Danenberg, John Carpten, Tanya Dorff, David Quinn, and Amir Goldkorn http://jci.me/125529

Human adipose tissue microvascular endothelial cells secrete PPARγ ligands and regulate adipose tissue lipid uptakeSilvia Gogg, Annika Nerstedt, Jan Boren, and Ulf Smith http://jci.me/125914

The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors p. 12Carolina Muguruza, Bastien Redon, Giulia R. Fois, Imane Hurel, Amandine Scocard, Claire Nguyen, Christopher Stevens, Edgar Soria-Gomez, Marjorie Varilh, Astrid Cannich, Justine Daniault, Arnau Busquets-Garcia, Teresa Pelliccia, Stéphanie Caillé, François Georges, Giovanni Marsicano, and Francis Chaouloff http://jci.me/126190

Single cell RNA sequencing identifies unique inflammatory airspace macrophage subsetsKara J. Mould, Nathan D. Jackson, Peter M. Henson, Max Seibold, and William J. Janssen http://jci.me/126556

Epigenetic modulation of β cells by interferon-α via PNPT1/mir-26a/TET2 triggers autoimmune diabetesMihaela Stefan-Lifshitz, Esra Karakose, Lingguang Cui, Abora Ettela, Zhengzi Yi, Weijia Zhang, and Yaron Tomer http://jci.me/126663

Angiotensin-converting enzyme inhibitors may affect pulmonary function in lymphangioleiomyomatosis p. 13Wendy K. Steagall, Mario Stylianou, Gustavo Pacheco-Rodriguez, and Joel Moss http://jci.me/126703

β Cell tone is defined by proglucagon peptides through cAMP signalingMegan E. Capozzi, Berit Svendsen, Sara E. Encisco, Sophie L. Lewandowski, Mackenzie D. Martin, Haopeng Lin, Justin L. Jaffe, Reilly W. Coch, Jonathan M. Haldeman, Patrick E. MacDonald, Matthew J. Merrins, David A. D’Alessio, and Jonathan E. Campbell http://jci.me/126742

CAMKII as a therapeutic target for growth factor–induced retinal and choroidal neovascularizationSadaf Ashraf, Samuel Bell, Caitriona O’Leary, Paul Canning, Ileana Micu, Jose A. Fernandez, Michael O’Hare, Peter Barabas, Hannah McCauley, Derek P. Brazil, Alan W. Stitt, J. Graham McGeown, and Tim M. Curtis http://jci.me/122442

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypesEllis Y. Kim, David Y. Barefield, Andy H. Vo, Anthony M. Gacita, Emma J. Schuster, Eugene J. Wyatt, Janel L. Davis, Biqin Dong, Cheng Sun, Patrick Page, Lisa Dellefave-Castillo, Alexis Demonbruen, Hao F. Zhang, and Elizabeth M. McNally (ASCI) http://jci.me/122686

Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in regulatory T cellsNicholas A.J. Dawson, Caroline Lamarche, Romy E. Hoeppli, Peter Bergqvist, Vivian C.W. Fung, Emma McIver, Qing Huang, Jana Gillies, Madeleine Speck, Paul C. Orban, Jonathan W. Bush, Majid Mojibian, and Megan K. Levings http://jci.me/123672

Treg gene signatures predict and measure type 1 diabetes trajectoryAnne M. Pesenacker, Virginia Chen, Jana Gillies, Cate Speake, Ashish K. Marwaha, Annika Sun, Samuel Chow, Rusung Tan, Thomas Elliott, Jan P. Dutz, Scott J. Tebbutt, and Megan K. Levings http://jci.me/123879

IL-33–mediated IL-13 secretion by ST2+ Tregs controls inflammation after lung injuryQuan Liu, Gaelen K. Dwyer, Yifei Zhao, Huihua Li, Lisa R. Mathews, Anish Bhaswantha Chakka, Uma R. Chandran, Jake A. Demetris, John F. Alcorn, Keven M. Robinson, Luis A. Ortiz, Bruce R. Pitt, Angus W. Thomson, Ming-Hui Fan, Timothy R. Billiar (ASCI), and Hēth R. Turnquist http://jci.me/123919

Secreted cellular prion protein binds doxorubicin and correlates with anthracycline resistance in breast cancerAdrian P. Wiegmans, Jodi M. Saunus, Sunyoung Ham, Richard Lobb, Jamie R. Kutasovic, Andrew J. Dalley, Mariska Miranda, Caroline Atkinson, Simote T. Foliaki, Kaltin Ferguson, Colleen Niland, Cameron N. Johnstone, Victoria Lewis, Steven J. Collins, Sunil R. Lakhani, Fares Al-Ejeh, and Andreas Möller http://jci.me/124092

Protection against Staphylococcus aureus bacteremia–induced mortality depends on ILC2s and eosinophilsPaulette A. Krishack, Tyler J. Louviere, Trevor S. Decker, Timothy G. Kuzel, Jared A. Greenberg, Daniel F. Camacho, Cara L. Hrusch, Anne I. Sperling, and Philip A. Verhoef http://jci.me/124168

Site-1 protease–derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capabilityFei Wang, Chuanming Xu, Renfei Luo, Kexin Peng, Nirupama Ramkumar, Shiying Xie, Xiaohan Lu, Long Zhao, Chang-Jiang Zuo, Donald E. Kohan, and Tianxin Yang http://jci.me/124174

A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapiesVéronique Bolduc, A. Reghan Foley, Herimela Solomon-Degefa, Apurva Sarathy, Sandra Donkervoort, Ying Hu, Grace S. Chen, Katherine Sizov, Matthew Nalls, Haiyan Zhou, Sara Aguti, Beryl B. Cummings, Monkol Lek, Taru Tukiainen, Jamie L. Marshall, Oded Regev, Dina Marek-Yagel, Anna Sarkozy, Russell J. Butterfield, Cristina Jou, Cecilia Jimenez-Mallebrera, Yan Li, Corine Gartioux, Kamel Mamchaoui, Valérie Allamand, Francesca Gualandi, Alessandra Ferlini, Eric Hanssen, the COL6A1 Intron 11 Study Group, Steve D. Wilton, Shireen R. Lamandé, Daniel G. MacArthur, Raimund Wagener, Francesco Muntoni, and Carsten G. Bönnemann http://jci.me/124403

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Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onsetYao Xiong, Kenneth Bedi, Simon Berritt, Bennette K. Attipoe, Thomas G. Brooks, Kevin Wang, Kenneth B. Margulies, and Jeffrey Field http://jci.me/124629

Different Munc18 proteins mediate baseline and stimulated airway mucin secretionAna M. Jaramillo, Lucia Piccotti, Walter V. Velasco, Anna Sofia Huerta Delgado, Zoulikha Azzegagh, Felicity Chung, Usman Nazeer, Junaid Farooq, Josh Brenner, Jan Parker-Thornburg, Brenton L. Scott, Christopher M. Evans, Roberto Adachi, Alan R. Burns, Silvia M. Kreda, Michael J. Tuvim, and Burton F. Dickey http://jci.me/124815

Sex-dependent factors encoded in the immune compartment dictate relapsing or progressive phenotype in demyelinating disease p. 11Tessa Dhaeze, Catherine Lachance, Laurence Tremblay, Camille Grasmuck, Lyne Bourbonnière, Sandra Larouche, Olivia Saint-Laurent, Marc-André Lécuyer, Rose-Marie Rébillard, Stephanie Zandee, and Alexandre Prat http://jci.me/124885

Longitudinal adaptive optics fluorescence microscopy reveals cellular mosaicism in patientsHaeWon Jung, Jianfei Liu, Tao Liu, Aman George, Margery G. Smelkinson, Sarah Cohen, Ruchi Sharma, Owen Schwartz, Arvydas Maminishkis, Kapil Bharti, Catherine Cukras, Laryssa A. Huryn, Brian P. Brooks, Robert Fariss, and Johnny Tam http://jci.me/124904

Transcriptional analysis of Foxp3+ Tregs and functions of two identified molecules during resolution of ALIJason R. Mock, Catherine F. Dial, Miriya K. Tune, Dustin L. Norton, Jessica R. Martin, John C. Gomez, Robert S. Hagan, Hong Dang, and Claire M. Doerschuk (ASCI) http://jci.me/124958

Cancer stem cell–associated miRNAs serve as prognostic biomarkers in colorectal cancerShusuke Toden, Shigeyasu Kunitoshi, Jacob Cardenas, Jinghua Gu, Elizabeth Hutchins, Kendall Van Keuren-Jensen, Hiroyuki Uetake, Yuji Toiyama, and Ajay Goel http://jci.me/125294

Lymphocyte mass cytometry identifies a CD3–CD4+ cell subset with a potential role in psoriasisRuru Guo, Ting Zhang, Xinyu Meng, Zhen Lin, Jinran Lin, Yu Gong, Xuesong Liu, Yuetian Yu, Guilin Zhao, Xianting Ding, Xiaoxiang Chen, and Liangjing Lu http://jci.me/125306

PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis p. 13Yan Geng, Xue Liu, Jiurong Liang, David Habiel, Kulur Vrishika, Ana Lucia Coelho, Nan Deng, Ting Xie, Yizhou Wang, Ningshan Liu, Guanling Huang, Adrianne Kurkciyan, Zhenqiu Liu, Jie Tang, Cory Hogaboam, Dianhua Jiang, and Paul W. Noble (ASCI) http://jci.me/125326

A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamicsMichael W. O’Reilly, Connar S.J. Westgate, Catherine Hornby, Hannah Botfield, Angela E. Taylor, Keira Markey, James L. Mitchell, William J. Scotton, Susan P. Mollan, Andreas Yiangou, Carl Jenkinson, Lorna C. Gilligan, Mark Sherlock, James Gibney, Jeremy W. Tomlinson, Gareth G. Lavery, David J. Hodson, Wiebke Arlt, and Alexandra J. Sinclair http://jci.me/125348

Skin cancer precursor immunotherapy for squamous cell carcinoma prevention p. 11Abby R. Rosenberg, Mary Tabacchi, Kenneth H. Ngo, Michael Wallendorf, Ilana S. Rosman, Lynn A. Cornelius, and Shadmehr Demehri http://jci.me/125476

An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosisJeremy Katzen, Brandie D. Wagner, Alessandro Venosa, Meghan Kopp, Yaniv Tomer, Scott J. Russo, Alvis C. Headen, Maria C. Basil, James M. Stark, Surafel Mulugeta, Robin R. Deterding, and Michael F. Beers http://jci.me/126125

High-resolution noncontact charge-density mapping of endocardial activationAndrew Grace, Stephan Willems, Christian Meyer, Atul Verma, Patrick Heck, Min Zhu, Xinwei Shi, Derrick Chou, Lam Dang, Christoph Scharf, Günter Scharf, and Graydon Beatty http://jci.me/126422

MicroRNA-155 coordinates the immunological landscape within murine melanoma and correlates with immunity in human cancersH. Atakan Ekiz, Thomas B. Huffaker, Allie H. Grossmann, W. Zac Stephens, Matthew A. Williams, June L. Round, and Ryan M. O’Connell http://jci.me/126543

Longitudinally persistent cerebrospinal fluid B cells can resist treatment in multiple sclerosis p. 11Ariele L. Greenfield, Ravi Dandekar, Akshaya Ramesh, Erica L. Eggers, Hao Wu, Sarah Laurent, William Harkin, Natalie S. Pierson, Martin S. Weber, Roland G. Henry, Antje Bischof, Bruce A.C. Cree, Stephen L. Hauser, Michael R. Wilson, and H.-Christian von Büdingen http://jci.me/126599

Sleeve gastrectomy rapidly enhances islet function independently of body weightJonathan D. Douros, Jingjing Niu, Sophia Sdao, Trillian Gregg, Kelsey Fisher-Wellman, Manish Bharadwaj, Anthony Molina, Ramamani Arumugam, MacKenzie Martin, Enrico Petretto, Matthew J. Merrins, Mark A. Herman, Jenny Tong, Jonathan Campbell, and David D’Alessio http://jci.me/126688

PD-L1 expression and tumor mutational burden are independent biomarkers in most cancersMark Yarchoan, Lee A. Albacker, Alexander C. Hopkins, Meagan Montesion, Karthikeyan Murugesan, Teena T. Vithayathil, Neeha Zaidi, Nilofer S. Azad, Daniel A. Laheru, Garrett M. Frampton, and Elizabeth M. Jaffee http://jci.me/126908

Myeloid folliculin balances mTOR activation to maintain innate immunity homeostasisJia Li, Shogo Wada, Lehn K. Weaver, Chhanda Biswas, Edward M. Behrens, and Zoltan Arany (ASCI) http://jci.me/126939

reviewAntibody-dependent and -independent mechanisms of inflammatory arthritisMargaret H. Chang and Peter A. Nigrovic (ASCI) http://jci.me/125278

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