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jci.org/this-month
ALSO IN THIS ISSUE:
Targeting mutant huntingtin toxicity 2
An immunoregulatory role for eosinophils 4
Remodeling lymphatic vessels in melanoma 6
JCI Insight 11
A summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
Scan with your mobile device for the digital version of JCI This Month.
September 2016
Transcription factor BCL6 is a druggable oncoprotein p. 1
This Month
Alejandro Aballay
Abul K. Abbas
Domenico Accili
Rexford S. Ahima
Qais Al-Awqati
Kari Alitalo
James Allison
Dario C. Altieri
Masayuki Amagai
Mark E. Anderson
Brian H. Annex
Alan Attie
Jane E. Aubin
Steven P. Balk
Michael F. Beers
John A. Belperio
Nina Bhardwaj
Morris J. Birnbaum
Joyce Bischoff
Mina J. Bissell
Craig Blackstone
Bruce R. Blazar
William A. Boisvert
Nancy Bonini
Brendan Boyce
Jonathan Bromberg
Frank C. Brosius
Hal E. Broxmeyer
Andrew Butler
Michael J. Caplan
Ruben D. Carrasco
Diego H. Castrillon
Harold Chapman
Ajay Chawla
Benjamin K. Chen
Benny J. Chen
Ju Chen
Marie-Françoise Chesselet
Vivian G. Cheung
Yongwon Choi
Thomas Clemens
Ronald G. Collman
Marco Colonna
George Cotsarelis
Shaun R. Coughlin
Christopher M. Counter
Peter D. Crompton
Tyler J. Curiel
David D’Alessio
Richard T. D’Aquila
Riccardo Dalla-Favera
Alan Daugherty
Ted Dawson
Sudhansu Dey
Harry C. Dietz III
Gianpietro Dotti
Michael Dustin
Connie J. Eaves
Dominique Eladari
Jack A. Elias
Joel K. Elmquist
Stephen G. Emerson
Jeffrey A. Engelman
Jonathan A. Epstein
Adrian Erlebacher
Joel D. Ernst
James M. Ervasti
Robert V. Farese Jr.
Eric R. Fearon
Edward A. Fisher
Susan Fisher
Richard A. Flavell
Tatiana Foroud
Velia M. Fowler
Martin Friedlander
Stephen J. Galli
J. Victor Garcia-Martinez
Alfred L. George Jr.
Stanton L. Gerson
Robert E. Gerszten
Todd Golde
Stanley Goldfarb
Larry B. Goldstein
Fred Sanford Gorelick
Kathleen J. Green
J. Timothy Greenamyre
Theresa A. Guise
David Hafler
Jonathan J. Hansen
Raymond C. Harris
Stanley L. Hazen
Peter Heeringa
Brian A. Hemmings
Meenhard Herlyn
Joachim Herz
Katherine A. High
Helen H. Hobbs
Ronald Hoffman
V. Michael Holers
Steven M. Holland
Michael J. Holtzman
Lawrence B. Holzman
Tamas L. Horvath
Gokhan S. Hotamisligil
Steven R. Houser
Scott J. Hultgren
Christopher A. Hunter
Ciro Indolfi
David E. James
William G. Kaelin Jr.
Klaus Kaestner
Mark L. Kahn
Raghu Kalluri
S. Ananth Karumanchi
Robert S. Kass
Masato Kasuga
Dontscho Kerjaschki
Sundeep Khosla
Richard N. Kitsis
Peter S. Klein
Steven Kliewer
Björn C. Knollmann
Walter J. Koch
Jay K. Kolls
Issei Komuro
Christopher D. Kontos
Murray Korc
Gary Koretzky
Calvin Kuo
Antonio La Cava
Fadi G. Lakkis
Terri Laufer
Mitchell A. Lazar
Brendan Lee
William M.F. Lee
Rudolph L. Leibel
Stanley M. Lemon
Jon D. Levine
Ross L. Levine
Klaus Ley
Richard M. Locksley
Gary Lopaschuk
Richard B. Mailman
Rama K. Mallampalli
Andrew R. Marks
Jack Martin
Steven O. Marx
Rodger P. McEver
Elizabeth McNally
Cornelius J. Melief
Shlomo Melmed
George Michalopoulos
Jeffrey H. Miner
Beverly Mitchell
Peter J. Mohler
Kelle Harbert Moley
Jeffery Molkentin
David D. Moore
Edward E. Morrisey
James H. Morrissey
Anthony J. Muslin
Martin G. Myers Jr.
Benjamin G. Neel
Eric N. Olson
Harry T. Orr
William C. Parks
Warren S. Pear
Sallie R. Permar
David J. Pinsky
Edward Plow
Jeffrey Pollard
Kornelia Polyak
Catherine Postic
Josef Prchal
Alice S. Prince
Louis J. Ptáček
Luigi Puglielli
Pere Puigserver
Bali Pulendran
Ellen Puré
Susan E. Quaggin
Marlene Rabinovitch
Daniel J. Rader
Shahin Rafii
Gwendalyn J. Randolph
Barbara Rehermann
Steven L. Reiner
Sarah A. Robertson
Paul B. Rosenberg
Theodora S. Ross
Marc E. Rothenberg
Anil Rustgi
J. Evan Sadler
Junichi Sadoshima
Jose-Alain Sahel
Jean E. Schaffer
Philipp E. Scherer
Michael D. Schneider
Detlef Schuppan
Michael W. Schwartz
William K. Scott
Randy Seeley
Amita Sehgal
Clay Semenkovich
Gregg L. Semenza
John Seykora
Steven D. Shapiro
Mari Shinohara
Steven E. Shoelson
Gerald I. Shulman
Journal of Clinical Investigation Consulting Editors
Roy L. Silverstein
M. Celeste Simon
Mihaela Skobe
Lois Smith
Steven R. Smith
Susan S. Smyth
Weihong Song
Ashley L. St. John
Herman F. Staats
Jonathan S. Stamler
John R. Stanley
Colin L. Stewart
Doris Stoffers
Warren Strober
Maureen A. Su
Katalin Susztak
Catharina Svanborg
Ira Tabas
Alan R. Tall
Sakae Tanaka
Victor J. Thannickal
Andrei Thomas-Tikhonenko
Georgia D. Tomaras
Peter Tontonoz
Laurence A. Turka
Raphael H. Valdivia
Marcel R.M. van den Brink
Luc Van Kaer
Matthias von Herrath
Yisong Y. Wan
Hong Wang
David Weinstock
Jeffrey Weiser
Stephen J. Weiss
Bart O. Williams
Joseph C. Wu
Thomas A. Wynn
Rudolf Zechner
Kang Zhang
Len Zon
Ming-Hui Zou
Weiping Zou
j c i . o r g / t h i s - m o n t h s e p t e m b e r 2 0 1 6 1
For the JCI and JCI InsightEditorHoward A. Rockman
Executive EditorSarah C. Jackson
Science EditorsJillian Hurst, Corinne Williams
For the JCIDeputy EditorsGarnett Kelsoe, Bryan L. Roth
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
Clinical Medicine Associate EditorsMichael A. Morse, Andrew J. Muir, Scott M. Palmer, Mark A. Stacy
Asia EditorDavid M. Virshup
Chair, Executive CouncilRobert J. Lefkowitz
BiostatisticiansCynthia Coffman, Maren Olsen
BioethicistArthur L. Caplan
Assistant Science EditorElyse Dankoski
Editor at LargeUshma S. Neill
ISSN 2324-7703 (print)ISSN 2325-4556 (online)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.
Contact the JCI and JCI Insight2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: [email protected] (JCI); [email protected] (JCI Insight)
For the full JCI online: jci.me/126/9 For JCI Insight: jci.me/insight/1/12jci.me/insight/1/13
This MonthSeptember 2016
A designer drug targets diffuse large B cell lymphomas
On the JCI cover
The BCL6 transcriptional repressor is a master regulator of germinal center formation and antibody affinity maturation. Constitutive expression of BCL6, through either chromosomal translocations or somatic mutations, contributes to the development of germinal center–type diffuse large B cell lymphomas (DLBCLs). While strategies aimed at inhibiting BCL6 are attractive in treating this subset of DLBCLs, transcription factors are notoriously poor pharmacological targets. In this issue of the JCI, a group of researchers led by Ari Melnick describe an in silico drug
design functional-group mapping approach to design a small molecule inhibitor with even higher affinity for BCL6 than its endogenous binding partner. The optimized compound, known as FX1, demonstrated superior binding with BCL6 than previously developed molecules, while also exhibiting a high degree of specificity for BCL6 over other BTB domain transcription factors. In mice, treatment with FX1 depleted germinal center B cells and, in 2 DLBCL xenograft models, caused tumor shrinkage. The researchers also found that FX1 inhibited primary tumor cell growth of non–germinal center DLBCLs, suggesting that BCL6 may be a broadly important target in DLBCLs, even in tumors expressing lower levels of the transcription factor. The cover image is a graphic depiction of FX1 (green) interacting with the BCL6 BTB domain lateral groove pocket and displacing its natural ligand. Image credit: Sam Shlomo Spaeth, CMI.
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphomaMariano G. Cardenas, Wenbo Yu, Wendy Beguelin, Matthew R. Teater, Huimin Geng, Rebecca L. Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyo Je Cho, Joshua Abbott, Wayne Tam, Wei Du, John P. Leonard, Olivier Elemento, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell Jr., and Ari M. Melnick http://jci.me/85795
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research
Editor’s picks
neuroscience
metabolism
Serine 421 phosphorylation mitigates toxicity of mutant Huntington’s proteinIn Huntington’s disease (HD), a mutant version of the HTT gene leads to neuronal dysfunction and degenera-tion, most prominently in the striatum, as well as motor, cognitive, and psychiatric dysfunction. Recent studies have shown that manipulations that increase phosphorylation of serine 421 (S421) in fragments of the mutant HTT protein can reduce its toxicity. Ian Kratter and colleagues investigated whether the S421 site regulates progressive neuro degeneration and behavioral deficits in a murine model of HD.
They expressed a human HTT that was altered either to mimic continuous S421 phosphorylation or to prevent S421 phosphorylation. Mimicking continuous S421 phosphorylation ameliorated neurodegeneration and behavioral dysfunction by increasing turnover of mutant HTT, leading to a reduction in levels of the toxic protein in striatal neurons (see the accompanying image). These data indicate that S421 is a potential target for therapeutic interventions for HD.
Serine 421 regulates mutant huntingtin toxicity and clearance in miceIan H. Kratter, Hengameh Zahed, Alice Lau, Andrey S. Tsvetkov, Aaron C. Daub, Kurt F. Weiberth, Xiaofeng Gu, Frédéric Saudou, Sandrine Humbert, X. William Yang, Alex Osmand, Joan S. Steffan, Eliezer Masliah, and Steven Finkbeiner http://jci.me/80339
Protein-diluted diet improves glucose homeostasis through liver signaling pathwaysAlthough high-protein diets have been linked to an increased incidence of type 2 diabetes, it is not known whether decreasing protein intake is an effective strategy for lowering the risk of developing obesity-related metabolic disorders. Adriano Maida and coworkers demonstrated that very-low-protein diets can increase metabolic health by improving glucose homeostasis in mice and humans. In nutritional and genetic murine models of obesity, a protein-diluted diet prevented impairments in glucose homeostasis and promoted metabolic inefficiency by inducing the liver integrated stress response–driven nuclear protein 1 (NUPR1) and liver-derived fibroblast growth factor 21 (FGF21). These data indicate that stress response pathways in the liver may mediate the protective effects of low-protein diets on obesity-related metabolic diseases.
A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilutionAdriano Maida, Annika Zota, Kim A. Sjøberg, Jonas Schumacher, Tjeerd P. Sijmonsma, Anja Pfenninger, Marie M. Christensen, Thomas Gantert, Jessica Fuhrmeister, Ulrike Rothermel, Dieter Schmoll, Mathias Heikenwälder, Juan L Iovanna, Kerstin Stemmer, Bente Kiens, Stephan Herzig, and Adam J. Rose http://jci.me/85946
j c i . o r g / t h i s - m o n t h s e p t e m b e r 2 0 1 6 3
JCI | Research: Editor’s picks
vascular biology
Calpain-6 mediates atherosclerotic accumulation of LDL in macrophagesIn atherosclerosis, macrophages form foam cells to deposit LDL cholesterol on vascular walls, leading to the formation of the plaques that cause lethal cardiovascular events. Although scavenger receptors mediate LDL uptake into macrophages, recent work suggests that independent mecha-nisms may also contribute to LDL accumulation. Takuro Miyazaki and coworkers investigated the role of calpain-6, an unconventional nonproteolytic isoform in the calpain protease family, in driving pinocytotic LDL uptake in atherogenic macrophages. Calpain-6 was required for LDL cholesterol uptake into macrophages as well as macrophage recruitment into atherosclerotic lesions, and calpain-6 deficiency in mice produced an atheroprotective phenotype in the aorta (see the accompanying image). Finally, evidence of calpain-6 induction in advanced human atherosclerotic vessels suggests that this molecule may be responsible for LDL uptake and deposition in advanced atherosclerosis.
Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicingTakuro Miyazaki, Kazuo Tonami, Shoji Hata, Toshihiro Aiuchi, Koji Ohnishi, Xiao-Feng Lei, Joo-ri Kim-Kaneyama, Motohiro Takeya, Hiroyuki Itabe, Hiroyuki Sorimachi, Hiroki Kurihara, and Akira Miyazaki http://jci.me/85880
Angiopoietin and Tie signaling drive vascular remodeling in inflammationBlood vessel remodeling is a central feature of developmental angiogenesis and plays key roles in inflammation and tumor growth. These changes in blood vessels depend on complex signaling through angiopoietins (ANG) and Tie receptors. ANG1 and ANG2 promote interactions between Tie1 and Tie2 that regulate changes in vessel structure, but the pathways that govern vessel stability or remodeling are not well understood. This month in the JCI, two studies investigate how ANG and Tie signaling control blood vessel homeostasis. Emilia Korhonen, Anita Lampinen, and colleagues determined that Tie1 acts as an intermediate in determining the effects of ANG1 and ANG2 on Tie2 signaling. Tie1 deficiency impaired the agonist action of ANG2 on Tie2 under
normal conditions, leading to decreased Tie2 phosphorylation that resembled its response to inflammatory states. Minah Kim and coworkers investigated the mechanisms enabling ANG2 to activate or inhibit Tie2. In normal conditions, ANG2 activated Tie2 to promote stable enlargement of blood vessels. However, in an infection-induced inflammatory state, ANG2 acted as an antagonist that drove vascular remodeling. Both studies found that cleavage of Tie1’s ectodomain during inflammation was associated with the switch of ANG2 from Tie2 agonist to antagonist. In the accompa-nying Commentary, Sarah Mueller and Christopher Kontos discuss ANG2/Tie1 interactions as an important control point in blood vessel remodeling under inflammatory conditions.
Related ResearchTie1 controls angiopoietin function in vascular remodeling and inflammationEmilia A. Korhonen, Anita Lampinen, Hemant Giri, Andrey Anisimov, Minah Kim, Breanna Allen, Shentong Fang, Gabriela D’Amico, Tuomas J. Sipilä, Marja Lohela, Tomas Strandin, Antti Vaheri, Seppo Ylä-Herttuala, Gou Young Koh, Donald M. McDonald, Kari Alitalo, and Pipsa Saharinen http://jci.me/84923
Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activationMinah Kim, Breanna Allen, Emilia A. Korhonen, Maximilian Nitschké, Hee Won Yang, Peter Baluk, Pipsa Saharinen, Kari Alitalo, Christopher Daly, Gavin Thurston, and Donald M. McDonald http://jci.me/84871
Related CommentaryTie1: an orphan receptor provides context for angiopoietin-2/Tie2 signalingSarah B. Mueller and Christopher D. Kontos http://jci.me/89963
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JCI | Research: Editor’s picks
otology
Aminoglycoside-induced hair cell death is driven by mitochondrial oxidation
Aminoglycoside antibiotics can cause irreversible damage to the hair cells of the inner ear. Although the mechanism of aminoglycoside-induced hair cell death is currently unknown, degeneration frequently occurs when reactive oxygen species (ROS) rise to toxic levels within the cochlea. Robert Esterberg and colleagues studied hair cells in the zebrafish lateral line to determine the origin of aminoglycoside-induced ROS and observed that oxidation levels in the mitochon-
dria and cytoplasm of dying cells correlated strongly with mitochondrial calcium uptake (see the accompanying image). Inhibition of mitochondrial calcium uptake protected hair cells against aminoglycoside-induced death. These findings further implicate ROS in aminoglycoside’s toxic effects and suggest that targeting mitochondrial calcium transporters may be an effective strategy for reducing aminoglycoside-induced hair cell damage.
Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell deathRobert Esterberg, Tor Linbo, Sarah B. Pickett, Patricia Wu, Henry C. Ou, Edwin W. Rubel, and David W. Raible http://jci.me/84939
immunology
Lung-resident eosinophils have a homeostatic function in allergic diseaseEosinophil production is increased in allergic diseases, and the inflammatory, Th2-associated actions of these immune cells can cause pathogenic tissue damage. However, increasing evidence suggests that eosinophils may also play a noninflam-matory role in regulating homeostatic immune functions. Claire Mesnil, Stéfanie Raulier, and colleagues characterized a subset of lung-resident eosinophils that display a regulatory profile and can inhibit the proallergic function of allergen-loaded DCs. Mice deficient for lung-resident eosinophils exhibited increased Th2 immunity in response to low doses of inhaled allergens, demonstrating a role for this subtype in the regulation of lung immune homeostasis. In the accompanying Commentary, Marc Rothenberg discusses how the identification of this lung-resident population adds to our understanding of eosinophils as an immunoregulatory cell population.
Lung-resident eosinophils represent a distinct regulatory eosinophil subsetClaire Mesnil, Stéfanie Raulier, Geneviève Paulissen, Xue Xiao, Mark A. Birrell, Dimitri Pirottin, Thibaut Janss, Philipp Starkl, Eve Ramery, Monique Henket, Florence N. Schleich, Marc Radermecker, Kris Thielemans, Laurent Gillet, Marc Thiry, Maria G. Belvisi, Renaud Louis, Christophe Desmet, Thomas Marichal, and Fabrice Bureau http://jci.me/85664
Related CommentaryA hidden residential cell in the lungMarc E. Rothenberg http://jci.me/89768
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JCI | Research: Editor’s picks
endocrinology
Ghrelin cell β1-adrenergic receptors regulate ghrelin secretion to prevent hypoglycemiaThe peptide hormone ghrelin is known to stimulate appetite and increase preference for calorie-dense foods. Ghrelin also increases blood glucose through multiple mechanisms, including modulation of insulin and glucagon secretion. Bharath Mani and coworkers observed that activation of β1-adrenergic receptors (β1ARs) on ghrelin-producing cells drives ghrelin secretion during caloric restriction. Ghrelin cell–specific β1AR-deficient mice exhibited impairments in ghrelin secretion and exaggerated hypoglycemia upon caloric restriction, which was reversed by ghrelin administration. Inhibition of β1AR activity with beta blockers similarly reduced ghrelin secretion and increased the incidence of hypoglycemia in calorie-restricted adolescent WT mice. These findings highlight a critical role for β1AR signaling in ghrelin secretion and its requirement in the maintenance of blood glucose levels, indicating a potential therapeutic use for ghrelin replacement in treating beta blocker–induced hypoglycemia.
β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individualsBharath K. Mani, Sherri Osborne-Lawrence, Prasanna Vijayaraghavan, Chelsea Hepler, and Jeffrey M. Zigman http://jci.me/86270
Disruptions in Gpr45 dysregulate POMC expression in murine obesity
Many of the genetic markers that have been linked to obesity risk involve neuropeptides that control food intake and energy expenditure, suggesting that dysfunctions in the pathways that regulate energy homeostasis may underlie some individuals’ predisposition to weight gain. Using a genetic screen for obesity-linked mutations in mice, Jing Cui and colleagues identified that disruptions in the gene encoding GPR45, a G protein–coupled
receptor, lead to increased adiposity, body mass, glucose intolerance, and hepatic steatosis (see the accompanying image). They determined that GPR45 drives expres-sion of the peptide POMC, which acts as a signal to regulate energy balance. These findings indicate that developing therapeutics to target GPR45 signaling could be an effective approach for combating obesity.
Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesityJing Cui, Yi Ding, Shu Chen, Xiaoqiang Zhu, Yichen Wu, Mingliang Zhang, Yaxin Zhao, Tong-Ruei R. Li, Ling V. Sun, Shimin Zhao, Yuan Zhuang, Weiping Jia, Lei Xue, Min Han, Tian Xu, and Xiaohui Wu http://jci.me/85676
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JCI | Research: Editor’s picks
gastroenterology
EGFR signaling drives macrophage-mediated chronic inflammation in bacterial infectionChronic inflammation induced by H. pylori infection creates a cycle of tissue and DNA damage that can lead to gastric cancer. This inflammation is driven in part by the activation of macrophages, which can mediate both proinflammatory and antiinflammatory responses to infection. Dana Hardbower and colleagues determined that macrophage activation and function during infection depend on signaling through the EGFR. EGFR deficiency exacerbated bacterial burden in mice infected with H. pylori and led to decreases in cytokine, chemokine, and NO production. Moreover, EGFR-deficient macrophages displayed impaired adaptive immune responses to infection, leading to a decrease in chronic inflammation (see the accompanying image). These findings suggest that targeting EGFR signaling is a potential intervention for chronic inflammation and carcinogenesis associated with H. pylori infection.
EGFR regulates macrophage activation and function in bacterial infectionDana M. Hardbower, Kshipra Singh, Mohammad Asim, Thomas G. Verriere, Danyvid Olivares-Villagómez, Daniel P. Barry, Margaret M. Allaman, M. Kay Washington, Richard M. Peek Jr., M. Blanca Piazuelo, and Keith T. Wilson http://jci.me/83585
angiogenesis
Local lymphatic remodeling determines immune responses to murine melanoma
Tumor-associated lymphatic vessels facilitate metastasis, yet they are also implicated in the immune cell trafficking that underlies antitumor adaptive immune responses. Amanda Lund, Marek Wagner, and colleagues determined that lymphatic vessels and their drainage are required for initiation of inflammation and immune responses against melanoma tumors. Unlike in normal mice, where melanoma growth occurs with leukocyte infiltration and suppressive cytokines, mice lacking dermal lymphatic vessels exhibited robust melanoma growth with marked reductions in cytokine expression and immune infiltrates. Without local lymphatics, metastasis was prevented (see the accompanying image), and adoptively transferred T cells were more effective.
These findings imply that lymphatics regulate both pro- and antitumor immune responses and suggest that the pathways regulating local lymphatic vessel remodeling and drainage may be potential therapeutic targets for improving responses to tumor-targeting immunotherapies.
Lymphatic vessels regulate immune microenvironments in human and murine melanomaAmanda W. Lund, Marek Wagner, Manuel Fankhauser, Eli S. Steinskog, Maria A. Broggi, Stefani Spranger, Thomas F. Gajewski, Kari Alitalo, Hans P. Eikesdal, Helge Wiig, and Melody A. Swartz http://jci.me/79434
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JCI | Features
reviews
conversations with giants in medicine
Alexander RudenskyAlexander Rudensky’s research has defined regulatory T cells and the roles they play in autoi mmunity, tolerance, allergies, infections, and cancer. After completing his PhD in Moscow in the early 1980s, Rudensky moved to the United States to study T cells under the mentorship of Charles Janeway. He is currently a professor of immunology at the Memorial Sloan Kettering Cancer Center. This month in the JCI, Ushma Neill interviews Dr. Rudensky about his childhood in the Soviet Union and his early interest in mathematics and science. He discusses the mentors and coworkers who have shaped his research interests over time, and speculates about the immunologi-cal discoveries we can expect in years to come. http://jci.me/89940
Kaposi sarcoma: understanding latency, infection, and reactivation
Bioactive fragments of the lung extracellular matrixThe extracellular matrix (ECM) serves as a cellular scaffold and plays a critical role in the maintenance of organ structure, the regulation of tissue development, cellular signaling, and mediation of cell-cell interactions. It undergoes continuous remodeling, with both synthesis of ECM components and proteolytic degradation. The fragments resulting from ECM degradation, known as matrikines, have been shown to promote immune cell infiltration, progressive tissue damage, and wound healing. In this issue, Amit Gaggar and Nathaniel Weathington review the role of matrikines in lung biology, focusing on fragments derived from collagen, hyaluronan, elastin, and laminin. Notably, several of these matrikines have been linked to lung disease and could potentially serve as biomarkers or therapeutic targets.
Bioactive extracellular matrix fragments in lung health and diseaseAmit Gaggar and Nathaniel Weathington http://jci.me/83147
Kaposi sarcoma (KS) is the most prevalent type of cancer affecting individuals living with HIV and AIDS, but the disease also occurs in HIV-negative adults and children. All cases of KS are linked to prior infection with the KS-associated herpesvirus (KSHV), a virus that can persist in a latent reservoir
for many years before reactivating and producing cancerous lesions. In spite of its lifelong persis-tence, only a small fraction of KSHV-infected individuals develop KS, usually in response to therapeutic or disease-related immune system suppression. In this issue of the JCI, Dirk Dittmer
and Blossom Damania review ongoing progress toward understanding the molecular mechanisms of KSHV infection, latency, and reactivation (see the accompanying image), as well as the insights this research provides about future clinical strategies for treating and preventing KS.
Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapyDirk P. Dittmer and Blossom Damania http://jci.me/84418
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Current research articles
angiogenesisLymphatic vessels regulate immune microenvironments in human and murine melanoma p. 6Amanda W. Lund, Marek Wagner, Manuel Fankhauser, Eli S. Steinskog, Maria A. Broggi, Stefani Spranger, Thomas F. Gajewski, Kari Alitalo, Hans P. Eikesdal, Helge Wiig, and Melody A. Swartz http://jci.me/79434
cardiologyTyrosine kinase FYN negatively regulates NOX4 in cardiac remodelingShouji Matsushima, Junya Kuroda, Peiyong Zhai, Tong Liu, Shohei Ikeda, Narayani Nagarajan, Shin-ichi Oka, Takashi Yokota, Shintaro Kinugawa, Chiao-Po Hsu, Hong Li, Hiroyuki Tsutsui, and Junichi Sadoshima http://jci.me/85624
endocrinologyRecurrent EZH1 mutations are a second hit in autonomous thyroid adenomasDavide Calebiro, Elisa S. Grassi, Markus Eszlinger, Cristina L. Ronchi, Amod Godbole, Kerstin Bathon, Fabiana Guizzardi, Tiziana de Filippis, Knut Krohn, Holger Jaeschke, Thomas Schwarzmayr, Rifat Bircan, Hulya Iliksu Gozu, Seda Sancak, Marek Niedziela, Tim M. Strom, Martin Fassnacht, Luca Persani, and Ralf Paschke http://jci.me/84894
Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity p. 5Jing Cui, Yi Ding, Shu Chen, Xiaoqiang Zhu, Yichen Wu, Mingliang Zhang, Yaxin Zhao, Tong-Ruei R. Li, Ling V. Sun, Shimin Zhao, Yuan Zhuang, Weiping Jia, Lei Xue, Min Han, Tian Xu, and Xiaohui Wu http://jci.me/85676
β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals p. 5Bharath K. Mani, Sherri Osborne-Lawrence, Prasanna Vijayaraghavan, Chelsea Hepler, and Jeffrey M. Zigman http://jci.me/86270
Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasisBrian T. O’Neill, Kevin Y. Lee, Katherine Klaus, Samir Softic, Megan T. Krumpoch, Joachim Fentz, Kristin I. Stanford, Matthew M. Robinson, Weikang Cai, Andre Kleinridders, Renata O. Pereira, Michael F. Hirshman, E. Dale Abel, Domenico Accili, Laurie J. Goodyear, K. Sreekumaran Nair, and C. Ronald Kahn http://jci.me/86522
gastroenterologyEGFR regulates macrophage activation and function in bacterial infection p. 6Dana M. Hardbower, Kshipra Singh, Mohammad Asim, Thomas G. Verriere, Danyvid Olivares-Villagómez, Daniel P. Barry, Margaret M. Allaman, M. Kay Washington, Richard M. Peek Jr., M. Blanca Piazuelo, and Keith T. Wilson http://jci.me/83585
geneticsPosttranscriptional manipulation of TERC reverses molecular hallmarks of telomere diseaseBaris Boyraz, Diane H. Moon, Matthew Segal, Maud Z. Muosieyiri, Asli Aykanat, Albert K. Tai, Patrick Cahan, and Suneet Agarwal http://jci.me/87547
Biallelic inactivation of REV7 is associated with Fanconi anemiaDominique Bluteau, Julien Masliah-Planchon, Connor Clairmont, Alix Rousseau, Raphael Ceccaldi, Catherine Dubois d’Enghien, Olivier Bluteau, Wendy Cuccuini, Stéphanie Gachet, Régis Peffault de Latour, Thierry Leblanc, Gérard Socié, André Baruchel, Dominique Stoppa-Lyonnet, Alan D. D’Andrea, and Jean Soulier http://jci.me/88010
immunologyLung-resident eosinophils represent a distinct regulatory eosinophil subset p. 4Claire Mesnil, Stéfanie Raulier, Geneviève Paulissen, Xue Xiao, Mark A. Birrell, Dimitri Pirottin, Thibaut Janss, Philipp Starkl, Eve Ramery, Monique Henket, Florence N. Schleich, Marc Radermecker, Kris Thielemans, Laurent Gillet, Marc Thiry, Maria G. Belvisi, Renaud Louis, Christophe Desmet, Thomas Marichal, and Fabrice Bureau http://jci.me/85664
BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy modelsYuki Kagoya, Munehide Nakatsugawa, Yuki Yamashita, Toshiki Ochi, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O. Butler, Cheryl H. Arrowsmith, and Naoto Hirano http://jci.me/86437
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inflammationLoss of ABCG1 influences regulatory T cell differentiation and atherosclerosisHsin-Yuan Cheng, Dalia E. Gaddis, Runpei Wu, Chantel McSkimming, LaTeira D. Haynes, Angela M. Taylor, Coleen A. McNamara, Mary Sorci-Thomas, and Catherine C. Hedrick http://jci.me/83136
Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injuryChristopher E. Pedigo, Gloria Michelle Ducasa, Farah Leclercq, Alexis Sloan, Alla Mitrofanova, Tahreem Hashmi, Judith Molina-David, Mengyuan Ge, Mariann I. Lassenius, Carol Forsblom, Markku Lehto, Per-Henrik Groop, Matthias Kretzler, Sean Eddy, Sebastian Martini, Heather Reich, Patricia Wahl, GianMarco Ghiggeri, Christian Faul, George W. Burke III, Oliver Kretz, Tobias B. Huber, Armando J. Mendez, Sandra Merscher, and Alessia Fornoni http://jci.me/85939
Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammationAdrian Achuthan, Andrew D. Cook, Ming-Chin Lee, Reem Saleh, Hsu-Wei Khiew, Melody W.N. Chang, Cynthia Louis, Andrew J. Fleetwood, Derek C. Lacey, Anne D. Christensen, Ashlee T. Frye, Pui Yeng Lam, Hitoshi Kusano, Koji Nomura, Nancy Steiner, Irmgard Förster, Stephen L. Nutt, Moshe Olshansky, Stephen J. Turner, and John A. Hamilton http://jci.me/87828
metabolismA liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution p. 2Adriano Maida, Annika Zota, Kim A. Sjøberg, Jonas Schumacher, Tjeerd P. Sijmonsma, Anja Pfenninger, Marie M. Christensen, Thomas Gantert, Jessica Fuhrmeister, Ulrike Rothermel, Dieter Schmoll, Mathias Heikenwälder, Juan L. Iovanna, Kerstin Stemmer, Bente Kiens, Stephan Herzig, and Adam J. Rose http://jci.me/85946
MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signalingByungyong Ahn, Mangala M. Soundarapandian, Hampton Sessions, Satyamaheshwar Peddihotla, Gregory P. Roth, Jian-Liang Li, Eliot Sugarman, Ada Koo, Siobhan Malany, Miao Wang, Kyungmoo Yea, Jeanne Brooks, Teresa C. Leone, Xianlin Han, Rick B. Vega, and Daniel P. Kelly http://jci.me/87382
muscle biologyPIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal modelsNesrin Sabha, Jonathan R. Volpatti, Hernan Gonorazky, Aaron Reifler, Ann E. Davidson, Xingli Li, Nadine M. Eltayeb, Claudia Dall’Armi, Gilbert Di Paolo, Susan V. Brooks, Ana Buj-Bello, Eva L. Feldman, and James J. Dowling http://jci.me/86841
nephrologyUrea impairs β cell glycolysis and insulin secretion in chronic kidney diseaseLaetitia Koppe, Elsa Nyam, Kevin Vivot, Jocelyn E. Manning Fox, Xiao-Qing Dai, Bich N. Nguyen, Dominique Trudel, Camille Attané, Valentine S. Moullé, Patrick E. MacDonald, Julien Ghislain, and Vincent Poitout http://jci.me/86181
neuroscienceSerine 421 regulates mutant huntingtin toxicity and clearance in mice p. 2Ian H. Kratter, Hengameh Zahed, Alice Lau, Andrey S. Tsvetkov, Aaron C. Daub, Kurt F. Weiberth, Xiaofeng Gu, Frédéric Saudou, Sandrine Humbert, X. William Yang, Alex Osmand, Joan S. Steffan, Eliezer Masliah, and Steven Finkbeiner http://jci.me/80339
oncologyZEB1 drives epithelial-to-mesenchymal transition in lung cancerJill E. Larsen, Vaishnavi Nathan, Jihan K. Osborne, Rebecca K. Farrow, Dhruba Deb, James P. Sullivan, Patrick D. Dospoy, Alexander Augustyn, Suzie K. Hight, Mitsuo Sato, Luc Girard, Carmen Behrens, Ignacio I. Wistuba, Adi F. Gazdar, Nicholas K. Hayward, and John D. Minna http://jci.me/76725
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma p. 1Mariano G. Cardenas, Wenbo Yu, Wendy Beguelin, Matthew R. Teater, Huimin Geng, Rebecca L. Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyo Je Cho, Joshua Abbott, Wayne Tam, Wei Du, John P. Leonard, Olivier Elemento, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell Jr., and Ari M. Melnick http://jci.me/85795
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JCI | Current research articles
oncologyMechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycinJianing Xu, Can G. Pham, Steven K. Albanese, Yiyu Dong, Toshinao Oyama, Chung-Han Lee, Vanessa Rodrik-Outmezguine, Zhan Yao, Song Han, David Chen, Daniel L. Parton, John D. Chodera, Neal Rosen, Emily H. Cheng, and James J. Hsieh http://jci.me/86120
Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cellsPartow Kebriaei, Harjeet Singh, M. Helen Huls, Matthew J. Figliola, Roland Bassett, Simon Olivares, Bipulendu Jena, Margaret J. Dawson, Pappanaicken R. Kumaresan, Shihuang Su, Sourindra Maiti, Jianling Dai, Branden Moriarity, Marie-Andrée Forget, Vladimir Senyukov, Aaron Orozco, Tingting Liu, Jessica McCarty, Rineka N. Jackson, Judy S. Moyes, Gabriela Rondon, Muzaffar Qazilbash, Stefan Ciurea, Amin Alousi, Yago Nieto, Katy Rezvani, David Marin, Uday Popat, Chitra Hosing, Elizabeth J. Shpall, Hagop Kantarjian, Michael Keating, William Wierda, Kim Anh Do, David A. Largaespada, Dean A. Lee, Perry B. Hackett, Richard E. Champlin, and Laurence J.N. Cooper http://jci.me/86721
Tumor immune profiling predicts response to anti–PD-1 therapy in human melanomaAdil I. Daud, Kimberly Loo, Mariela L. Pauli, Robert Sanchez-Rodriguez, Priscila Munoz Sandoval, Keyon Taravati, Katy Tsai, Adi Nosrati, Lorenzo Nardo, Michael D. Alvarado, Alain P. Algazi, Miguel H. Pampaloni, Iryna V. Lobach, Jimmy Hwang, Robert H. Pierce, Iris K. Gratz, Matthew F. Krummel, and Michael D. Rosenblum http://jci.me/87324
otologyMitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death p. 4Robert Esterberg, Tor Linbo, Sarah B. Pickett, Patricia Wu, Henry C. Ou, Edwin W. Rubel, and David W. Raible http://jci.me/84939
stem cellsBRPF1 is essential for development of fetal hematopoietic stem cellsLinya You, Lin Li, Jinfeng Zou, Kezhi Yan, Jad Belle, Anastasia Nijnik, Edwin Wang, and Xiang-Jiao Yang http://jci.me/80711
transplantationA colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host diseaseVivian Zhou, Kimberle Agle, Xiao Chen, Amy Beres, Richard Komorowski, Ludovic Belle, Carolyn Taylor, Fenlu Zhu, Dipica Haribhai, Calvin B. Williams, James Verbsky, Wendy Blumenschein, Svetlana Sadekova, Eddie Bowman, Christie Ballantyne, Casey Weaver, David A. Serody, Benjamin Vincent, Jonathan Serody, Daniel J. Cua, and William R. Drobyski http://jci.me/80874
vascular biologyOpposing actions of agiopoietin-2 on Tie2 signaling and FOXO1 activation p. 3Minah Kim, Breanna Allen, Emilia A. Korhonen, Maximilian Nitschké, Hee Won Yang, Peter Baluk, Pipsa Saharinen, Kari Alitalo, Christopher Daly, Gavin Thurston, and Donald M. McDonald http://jci.me/84871
Tie1 controls angiopoietin function in vascular remodeling and inflammation p. 3Emilia A. Korhonen, Anita Lampinen, Hemant Giri, Andrey Anisimov, Minah Kim, Breanna Allen, Shentong Fang, Gabriela D’Amico, Tuomas J. Sipilä, Marja Lohela, Tomas Strandin, Antti Vaheri, Seppo Ylä-Herttuala, Gou Young Koh, Donald M. McDonald, Kari Alitalo, and Pipsa Saharinen http://jci.me/84923
Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing p. 3Takuro Miyazaki, Kazuo Tonami, Shoji Hata, Toshihiro Aiuchi, Koji Ohnishi, Xiao-Feng Lei, Joo-ri Kim-Kaneyama, Motohiro Takeya, Hiroyuki Itabe, Hiroyuki Sorimachi, Hiroki Kurihara, and Akira Miyazaki http://jci.me/85880
Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertensionChristophe Guignabert, Carole Phan, Andrei Seferian, Alice Huertas, Ly Tu, Raphaël Thuillet, Caroline Sattler, Morane Le Hiress, Yuichi Tamura, Etienne-Marie Jutant, Marie-Camille Chaumais, Stéphane Bouchet, Benjamin Manéglier, Mathieu Molimard, Philippe Rousselot, Olivier Sitbon, Gérald Simonneau, David Montani, and Marc Humbert http://jci.me/86249
Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertensionThomas Bertero, William M. Oldham, Katherine A. Cottrill, Sabrina Pisano, Rebecca R. Vanderpool, Qiujun Yu, Jingsi Zhao, Yiyin Tai, Ying Tang, Ying-Yi Zhang, Sofiya Rehman, Masataka Sugahara, Zhi Qi, John Gorcsan III, Sara O. Vargas, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Kathleen J. Haley, Aaron B. Waxman, Victoria N. Parikh, Teresa De Marco, Priscilla Y. Hsue, Alison Morris, Marc A. Simon, Karen A. Norris, Cedric Gaggioli, Joseph Loscalzo, Joshua Fessel, and Stephen Y. Chan http://jci.me/86387
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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 [email protected]
Editor’s picks
inflammation
Aldehyde dehydrogenase mediates ocular mucosa fibrosisFibrotic scarring of the ocular mucosa causes blindness and is associated with ocular pemphigoid, trachoma, and allergic eye disease (AED). Two independent research groups led by Daniel Saban and John Dart demonstrate that the aldehyde dehydrogenase (ALDH) metabolite retinoic acid (RA) mediates ocular mucosal fibrosis. Using a murine model of AED, Saban and colleagues demonstrated that DCs directly induce fibrosis through ALDH production of RA, which activates the retinoid X receptor (RXR) in conjunctival fibroblasts. RXR stimulation rapidly induced ocular mucosal fibrosis, while inhibition of ALDH activity or depletion of DCs markedly reduced fibrosis in mice. Dart and colleagues found that ALDH1 family members were upregu-lated in the conjunctiva of patients with ocular mucous membrane pemphigoid (OMMP), as well as in cultured patient fibroblasts. Treatment of cultured patient fibroblasts with the ALDH1 inhibitor disulfiram reduced collagen production, increased matrix contraction and proliferation, and altered actin organization. Moreover, topical disulfiram treatment attenuated
ocular inflammation and fibrosis in a murine AED model. Taken together, these findings delineate mechanisms mediating ocular fibrosis and identify potential therapeutic targets.
Related ResearchAldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarringSarah D. Ahadome, David J. Abraham, Suryanarayana Rayapureddi, Valerie P. Saw, Daniel R. Saban, Virginia L. Calder, Jill T. Norman, Markella Ponticos, Julie T. Daniels, and John K. Dart http://jci.me/87001
Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergySarah D. Ahadome, Rose Mathew, Nancy J. Reyes, Priyatham S. Mettu, Scott W. Cousins, Virginia L. Calder, and Daniel R. Saban http://jci.me/87012
Heart-resident macrophages drive neutrophil trafficking in cardiac ischemia-reperfusion injuryMyocardial ischemia-reperfusion injury, such as occurs after cardiopulmonary bypass operations or heart transplant, triggers cardiomyocyte death, resulting in impaired heart function. Neutrophil infiltration of the heart is known to promote damage, but the underlying mechanisms governing neutrophil trafficking are unclear. Using a murine model of cardiac transplant ischemia-reperfusion and two-photon microscopy, Wenjun Li, Hsi-Min Hsiao, and colleagues show that tissue-resident CCR2+ macrophages mediate neutrophil recruitment (see the accompanying image). Mechanisti-cally, cardiac cell death results in the release of damage-associated molecular patterns, which activate a TLR9/MyD88 pathway in CCR2+ macrophages. This pathway mediates the release of the chemoattractants CXCL2 and CXCL5, which induce neutrophil adhesion and crawling, respectively, ultimately leading to extravasation and migration into the heart.
Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signalingWenjun Li, Hsi-Min Hsiao, Ryuji Higashikubo, Brian T. Saunders, Ankit Bharat, Daniel R. Goldstein, Alexander S. Krupnick, Andrew E. Gelman, Kory J. Lavine, and Daniel Kreisel http://jci.me/87315
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JCI Insight | Editor’s picks
nephrology
Metalloprotease ADAM17 mediates profibrotic factor release in the kidneyKidney fibrosis is a frequent consequence of kidney injury or disease and can result in nephron loss and eventual kidney failure. Eirini Kefaloyianni and colleagues demonstrate that the metalloprotease ADAM17 is upregulated after kidney injury and mediates the release of pro-TNFα and the EGFR ligand amphiregulin in the proximal tubule. Deletion of Adam17 within the proximal tubule or treatment with an ADAM17 inhibitor protected against fibrosis after acute kidney injury (AKI; see the accompanying image) or unilateral ureter obstruction (UUO) in mice. Importantly, soluble amphiregulin levels were elevated in urine samples from patients with AKI or chronic kidney disease, and ADAM17 and amphiregulin expression in kidney biopsies strongly correlated with markers of fibrosis, indicating that ADAM17 drives fibrosis in human kidney fibrosis.
ADAM17 substrate release in proximal tubule drives kidney fibrosisEirini Kefaloyianni, Muthu Lakshmi Muthu, Jakob Kaeppler, Xiaoming Sun, Venkata Sabbisetti, Athena Chalaris, Stefan Rose-John, Eitan Wong, Irit Sagi, Sushrut S. Waikar, Helmut Rennke, Benjamin D. Humphreys, Joseph V. Bonventre, and Andreas Herrlich http://jci.me/87023
oncology
PAX8/chromatin interactions are dramatically altered in serous ovarian carcinomasMost high-grade serous ovarian carcinomas (HGSOCs) arise from fallopian tube secretory epithelial cells (FTSECs). PAX8 is a lineage-restricted transcription factor (TF) of the Müllerian epithe-lium. It gives rise to the female reproductive tract and is retained in nearly all HGSOCs. Kevin Elias and colleagues investigated alterations in the epigenetic behavior of PAX8 between FTSECs and HGSOCs. Using whole transcriptome shotgun sequencing (RNA-seq) and ChIP-seq, Elias and colleagues showed that the cistromes between FTSEC and HGSOC lines are radically altered. Additionally,
genes that were significantly altered between FTSECs and HGSOCs were clustered around PAX8 binding sites. The differentially regulated genes were also near binding sites for the TEAD family of transcription factors, which mediate YAP-depen-dent gene induction and have been implicated in FTSEC/HGSOC transformation. Coimmunoprecipi-tation and proximity ligation assays confirmed that PAX8 and TEAD TFs physically interact in Müllerian cells. These results suggest that the development of HGSOC is linked to PAX8/TEAD-mediated interactions with chromatin.
Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursorsKevin M. Elias, Megan M. Emori, Thomas Westerling, Henry Long, Anna Budina-Kolomets, Fugen Li, Emily MacDuffie, Michelle R. Davis, Alexander Holman, Brian Lawney, Matthew L. Freedman, John Quackenbush, Myles Brown, and Ronny Drapkin http://jci.me/87988
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JCI Insight | Editor’s picks
autoimmunity
A D V E R T I S E M E N T
IL4 receptor-α deficiency impairs T cell egress in murine systemic sclerosis
Systemic sclerosis (SSc) is a fatal autoimmune disease characterized by inflammation and fibrosis of internal organs and the skin. Because mice deficient in IL4 receptor-α (IL4RA) are protected in a murine model of SSc (sclerodermatous graft versus host disease), Katia Urso and colleagues examined the mechanisms underlying this protection. They found that IL4RA deficiency resulted in decreased levels of the sphingosine-1 phosphate–producing (S1P-producing) enzyme sphingosine kinase 1 (SPHK1) in the lymphatic endothelial cells of the draining lymph nodes (dLNs). Impaired S1P production altered the efferent lymphatics morphology and resulted in retention of effector T cells in skin dLNs (see the accompanying image). Intravenous injection of effector T cells, which bypasses the efferent lymphatics, induced SSc-like symptoms in IL4RA-deficient mice. These findings reveal a role for IL4RA in T cell egress that could potentially serve as a therapeutic target in SSc.
IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host diseaseKatia Urso, David Alvarez, Viviana Cremasco, Kelly Tsang, Angelo Grauel, Robert Lafyatis, Ulrich H. von Andrian, Joerg Ermann, and Antonios O. Aliprantis http://jci.me/88057
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Identification of microRNA-181a-5p and microRNA-4454 as mediators of facet cartilage degenerationAkihiro Nakamura, Y. Raja Rampersaud, Anirudh Sharma, Stephen J. Lewis, Brian Wu, Poulami Datta, Kala Sundararajan, Helal Endisha, Evgeny Rossomacha, Jason S. Rockel, Igor Jurisica, and Mohit Kapoor http://jci.me/86820
Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring p. 11Sarah D. Ahadome, David J. Abraham, Suryanarayana Rayapureddi, Valerie P. Saw, Daniel R. Saban, Virginia L. Calder, Jill T. Norman, Markella Ponticos, Julie T. Daniels, and John K. Dart http://jci.me/87001
A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human bloodLiudmila L. Mazaleuskaya, John A. Lawson, Xuanwen Li, Gregory Grant, Clementina Mesaros, Tilo Grosser, Ian A. Blair, Emanuela Ricciotti, and Garret A. FitzGerald http://jci.me/87031
FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalitiesRana Rais, Weiwei Jiang, Huihong Zhai, Krystyna M. Wozniak, Marigo Stathis, Kristen R. Hollinger, Ajit G.Thomas, Camilo Rojas, James J. Vornov, Michael Marohn, Xuhang Li, and Barbara S. Slusher http://jci.me/88634
Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling p. 11Wenjun Li, Hsi-Min Hsiao, Ryuji Higashikubo, Brian T. Saunders, Ankit Bharat, Daniel R. Goldstein, Alexander S. Krupnick, Andrew E. Gelman, Kory J. Lavine, and Daniel Kreisel http://jci.me/87315
Elimination of p19ARF-expressing cells enhances pulmonary function in miceMichihiro Hashimoto, Azusa Asai, Hiroyuki Kawagishi, Ryuta Mikawa, Yuji Iwashita, Kazuki Kanayama, Kazushi Sugimoto, Tadashi Sato, Mitsuo Maruyama, and Masataka Sugimoto http://jci.me/87732
IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease p. 13Katia Urso, David Alvarez, Viviana Cremasco, Kelly Tsang, Angelo Grauel, Robert Lafyatis, Ulrich H. von Andrian, Joerg Ermann, and Antonios O. Aliprantis http://jci.me/88057
Increased mitochondrial DNA deletions and copy number in transfusion-dependent thalassemiaAshutosh Lal, Esteban Gomez, and Cassandra Calloway http://jci.me/88150
HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolatesChristopher D. Petro, Brian Weinrick, Nazanin Khajoueinejad, Clare Burn, Rani Sellers, William R. Jacobs Jr., and Betsy C. Herold http://jci.me/88529
Cartilage degeneration
GCPII inhibition in colitis
HSV-infected skin
Current research articles
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Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy p. 11Sarah D. Ahadome, Rose Mathew, Nancy J. Reyes, Priyatham S. Mettu, Scott W. Cousins, Virginia L. Calder, and Daniel R. Saban http://jci.me/87012
Decreases in thymopoiesis of astronauts returning from space flightCara L. Benjamin, Raymond P. Stowe, Lisa St. John, Clarence F. Sams, Satish K. Mehta, Brian E. Crucian, Duane L. Pierson, and Krishna V. Komanduri http://jci.me/88787
Quantum coherence spectroscopy to measure dietary fat retention in the liverLucas Lindeboom, Robin A. de Graaf, Christine I. Nabuurs, Petronella A. van Ewijk, Matthijs K.C. Hesselink, Joachim E. Wildberger, Patrick Schrauwen, and Vera B. Schrauwen-Hinderling http://jci.me/84671
A cord blood monocyte–derived cell therapy product accelerates brain remyelinationArjun Saha, Susan Buntz, Paula Scotland, Li Xu, Pamela Noeldner, Sachit Patel, Amy Wollish, Aruni Gunaratne, Tracy Gentry, Jesse Troy, Glenn K. Matsushima, Joanne Kurtzberg, and Andrew E. Balber http://jci.me/86667
ADAM17 substrate release in proximal tubule drives kidney fibrosis p. 12Eirini Kefaloyianni, Muthu Lakshmi Muthu, Jakob Kaeppler, Xiaoming Sun, Venkata Sabbisetti, Athena Chalaris, Stefan Rose-John, Eitan Wong, Irit Sagi, Sushrut S. Waikar, Helmut Rennke, Benjamin D. Humphreys, Joseph V. Bonventre, and Andreas Herrlich http://jci.me/87023
Characterization of candidate genes in inflammatory bowel disease-associated risk lociJoanna M. Peloquin, Gautam Goel, Lingjia Kong, Hailiang Huang, Talin Haritunians, R. Balfour Sartor, Mark J. Daly, Rodney D. Newberry, Dermot P. McGovern, Vijay Yajnik, Sergio A. Lira, and Ramnik J. Xavier http://jci.me/87899
Thermogenic profiling using magnetic resonance imaging of dermal and other adipose tissuesIldiko Kasza, Diego Hernando, Alejandro Roldán-Alzate, Caroline M. Alexander, and Scott B. Reeder http://jci.me/87146
Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors p. 12Kevin M. Elias, Megan M. Emori, Thomas Westerling, Henry Long, Anna Budina-Kolomets, Fugen Li, Emily MacDuffie, Michelle R. Davis, Alexander Holman, Brian Lawney, Matthew L. Freedman, John Quackenbush, Myles Brown, and Ronny Drapkin http://jci.me/87988
Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosisAnna Cline-Smith, Jesse Gibbs, Elena Shashkova, Zachary S. Buchwald, Deborah V. Novack, and Rajeev Aurora http://jci.me/88839
Ocular mucosal fibrosis
Cord blood monocytes in brain
Dermal white adipose tissue
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JCI Insight | Current research articles
Gene pathway development in human epicardial adipose tissue during early lifeShalini Ojha, Hernan P. Fainberg, Victoria Wilson, Giuseppe Pelella, Marcos Castellanos,Sean T. May, Attilio A. Lotto, Harold Sacks, Michael E. Symonds, and Helen Budge http://jci.me/87460
Zika virus productively infects primary human placenta-specific macrophagesKellie Ann Jurado, Michael K. Simoni, Zhonghua Tang, Ryuta Uraki, Jesse Hwang, Sarah Householder, Mingjie Wu, Brett D. Lindenbach, Vikki M. Abrahams, Seth Guller, and Erol Fikrig http://jci.me/88461
Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophyElise M.N. Ferre, Stacey R. Rose, Sergio D. Rosenzweig, Peter D. Burbelo, Kimberly R. Romito, Julie E. Niemela, Lindsey B. Rosen, Timothy J. Break, Wenjuan Gu, Sally Hunsberger, Sarah K. Browne, Amy P. Hsu, Shakuntala Rampertaap, Muthulekha Swamydas, Amanda L. Collar, Heidi H. Kong, Chyi-Chia Richard Lee, David Chascsa, Thomas Simcox, Angela Pham, Anamaria Bondici, Mukil Natarajan, Joseph Monsale, David E. Kleiner, Martha Quezado, Ilias Alevizos, Niki M. Moutsopoulos, Lynne Yockey, Cathleen Frein, Ariane Soldatos, Katherine R. Calvo, Jennifer Adjemian, Morgan N. Similuk, David M. Lang, Kelly D. Stone, Gulbu Uzel, Jeffrey B. Kopp, Rachel J. Bishop, Steven M. Holland, Kenneth N. Olivier, Thomas A. Fleisher, Theo Heller, Karen K. Winer, and Michail S. Lionakis http://jci.me/88782
Airway epithelial homeostasis and planar cell polarity signaling depend on multiciliated cell differentiationEszter K. Vladar, Jayakar V. Nayak, Carlos E. Milla, and Jeffrey D. Axelrod http://jci.me/88027
Zika-infected placental macrophages
Cystic fibrosis epithelia
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
