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jci.org/this-month
ALSO IN THIS ISSUE:
Complement activation complicates anti-VEGF therapy 2
Cardiac myofibroblasts clean up after myocardial infarction 4
TGF-β1 promotes recovery after acute brain injury 6
Blocking type I interferon boosts antiretroviral therapy 6
Review Series: Metabolism and inflammation edited by Alan R. Saltiel and Jerrold M. Olefsky 8
JCI Insight 12
A summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
Scan with your mobile device for the digital version of JCI This Month.
January 2017 Metastatic vesicle trafficking in EMT p. 1
This Month
Christopher M. Adams
Maria-Luisa Alegre
Ravi K. Amaravadi
John K. Amory
Jennifer H. Anolik
Cristian Apetrei
Rajendra S. Apte
Zoltan Arany
Hossein Ardehali
Kenneth I. Ataga
Joseph Bass
Alexander G. Bassuk
Antonio C. Bianco
Jonathan S. Bogan
Laura M. Bohn
Nunzio Bottini
Sebastien G. Bouret
Jason Brenchley
Renier J. Brentjens
G.R. Scott Budinger
George A. Calin
Stephen Chan
Yuan Chang
Zhou-Feng Chen
Keith A. Choate
Wendy Chung
Craig M. Coopersmith
George Cotsarelis
Peter Crawford
Lisa L. Cunningham
Ronald P. DeMatteo
Elia J. Duh
Sarah K. England
Mark W. Feinberg
John H. Fingert
Robert Flaumenhaft
Edward A. Fon
Lawrence Fong
Nikolaos G. Frangogiannis
Anthony R. French
Terrence L. Geiger
Noyan Gokce
Raphaela Goldbach-Mansky
Daniel R. Goldstein
Douglas K. Graham
Khalid A. Hanafy
Eric B. Haura
John Cijiang He
Robert O. Heuckeroth
Cory M. Hogaboam
Young-Kwon Hong
Benjamin D. Humphreys
Ken Inoki
Shingo Kajimura
Pawel Kalinski
John Y. Kao
Mariana J. Kaplan
Michael G. Kaplitt
Barbara I. Kazmierczak
Hans-Peter Kiem
William Y. Kim
David G. Kirsch
Mathias Lichterfeld
André Lieber
Michail S. Lionakis
Carey N. Lumeng
Leo Luznik
Ivan Maillard
Ziad Mallat
Peter Mannon
Franck Mauvais-Jarvis
Dermot P.B. McGovern
Borna Mehrad
Ingo K. Mellinghoff
Jason C. Mills
Joshua D. Milner
Satdarshan (Paul) Singh Monga
Hidayatullah G. Munshi
Matthias Nahrendorf
Mary Nakamura
Lisa F.P. Ng
Mark Nicolls
Laura J. Niedernhofer
Deborah V. Novack
S. Tiong Ong
Puneet Opal
Daniel Ory
Sophie Paczesny
Stephanie T. Page
Mary-Elizabeth Patti
Janos Peti-Peterdi
Fernando P. Polack
Matthew D. Ringel
Steven M. Rowe
Svati H. Shah
Vijay H. Shah
Alice T. Shaw
Rhonda F. Souza
Fayyaz S. Sutterwala
Shu Takeda
Natalie J. Torok
Stephen H. Tsang
Ellie Tzima
Mark C. Udey
Fumihiko Urano
Charles P. Venditti
Joseph M. Vinetz
Sing Sing Way
Bernd Wollnik
Minna Woo
Prescott G. Woodruff
Lori M. Zeltser
Yutong Zhao
Binhua P. Zhou
JCI Insight Consulting Editors
1j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 7
EditorHoward A. Rockman
Executive EditorSarah C. Jackson
Science EditorsJillian Hurst, Corinne Williams
Assistant Science EditorElyse Dankoski
Deputy 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
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/127/1 For JCI Insight: jci.me/insight/1/20jci.me/insight/1/21
This MonthJanuary 2017
Metastatic vesicle trafficking during the epithelial-to-mesenchymal transition
On the JCI cover
The conversion of polarized epithelial cells into mesenchymal cells that migrate and invade the extracel-lular matrix, known as epithelial-to-mesenchymal transition (EMT), drives metastasis of epithelial cancers. During this shift, secretory vesicle trafficking is redirected toward the leading edge of the cell, promoting the formation of promigratory focal adhesions and cytoplasmic protrusions as well as the release of factors that drive extracellular matrix remodeling and angiogenesis. In this issue of the
JCI, a research team led by Jonathan Kurie uncovered a role for Golgi apparatus compaction in regulating vesicle trafficking during EMT. Golgi structural features were quantified during EMT in a metastatic lung adenocarcinoma model, and it was found that metastatic mesenchymal cells had enhanced Golgi organelle com-paction. Forced expression of ZEB1, which promotes EMT, also led to Golgi com-paction in multiple in vitro models. Transcriptional profiling of ZEB1-expressing cells suggested that the scaffolding protein PAQR11, which assembles multipro-tein complexes in the Golgi, was a key mediator of Golgi reorganization. Accord-ingly, increased expression of PAQR11 was associated with decreased survival in lung adenocarcinoma patients, and knockdown of PAQR11 impaired migration and invasion of lung adenocarcinoma cells. Together, these findings reveal an important role for PAQR11 in promoting cell motility, invasion, and metastasis during EMT. The accompanying image shows a normal bronchus within a human lung adenocarcinoma tissue section costained with DAPI (magenta) and antibod-ies against the Golgi protein GM130 (yellow) and collagen I (blue).
Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11Xiaochao Tan, Priyam Banerjee, Hou-Fu Guo, Stephen Ireland, Daniela Pankova, Young-ho Ahn, Irodotos Michail Nikolaidis, Xin Liu, Yanbin Zhao, Yongming Xue, Alan R. Burns, Jonathon Roybal, Don L. Gibbons, Tomasz Zal, Chad J. Creighton, Daniel Ungar, Yanzhuang Wang, and Jonathan M. Kurie http://jci.me/88736
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research
Editor’s picks
VEGF regulates deleterious complement activation in the retinaVEGF signaling maintains specialized vasculature that supports the functions of the outer retina, but elevated VEGF levels are linked to neovascularization and vision loss in patients with wet age-related macular degeneration (ARMD). Anti-VEGF therapies can be used to stabilize or improve vision, but some patients’ vision continues to deteriorate during treatment. Lindsay Keir and colleagues investigated whether anti-VEGF therapies perpetuate damage in nonresponsive patients by activating the complement system. There is evidence that genetic variation in complement factor H (CFH) contributes to poor response to anti-VEGF therapies in wet ARMD patients, and the researchers observed that cells expressing CFH polymorphisms displayed high levels of complement deposits, an effect that was exacerbated by VEGF antagonism (see the accompanying image). These findings support a link between VEGF signaling and complement activation that may explain inadequate outcomes of anti-VEGF therapy in some wet ARMD patients.
nephrology
VEGF regulates local inhibitory complement proteins in the eye and kidneyLindsay S. Keir, Rachel Firth, Lyndsey Aponik, Daniel Feitelberg, Susumu Sakimoto, Edith Aguilar, Gavin I. Welsh, Anna Richards, Yoshihiko Usui, Simon C. Satchell, Valeryia Kuzmuk, Richard J. Coward, Jonathan Goult, Katherine R. Bull, Ruchi Sharma, Kapil Bharti, Peter D. Westenskow, Iacovos P. Michael, Moin A. Saleem, and Martin Friedlander http://jci.me/86418
Prader-Willi syndrome (PWS) results from paternal deletion of a region encompassing multiple genes, including the noncoding RNA SNORD116. Individuals with PWS display hyperphagic obesity and neuroendocrine dysfunction, including abnormally low levels of growth hormone (GH) and insulin and high levels of the “hunger hormone” ghrelin. Lisa Cole Burnett and colleagues observed that the expression of two genes involved in prohormone processing, Nhlh2 and Pcsk1, are downregulated in PWS iPSC-derived neurons and in hypothalami of mice segregating for a paternal deletion of
endocrinology
Defective prohormone processing contributes to neuroendocrine dysfunction in Prader-Willi syndrome
Snord116 (Snord116p–/m+ mice). These mice recapitulate many of the neuroendocrine and behavioral phenotypes of patients with PWS. The authors showed that Snord116p–/m+ mice also displayed functional defects in proinsulin, proGH-releasing hormone, and proghrelin processing that were linked to reductions in the protein product of Pcsk1, the prohormone convertase PC1. In the accompanying Commen-tary, Joseph Polex-Wolf, Giles Yeo, and Stephen O’Rahilly discuss the implication that PC1 deficiency is a mechanism underlying the major neuroendocrine phenotypes of PWS.
Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndromeLisa C. Burnett, Charles A. LeDuc, Carlos R. Sulsona, Daniel Paull, Richard Rausch, Sanaa Eddiry, Jayne F. Martin Carli, Michael V. Morabito, Alicja A. Skowronski, Gabriela Hubner, Matthew Zimmer, Liheng Wang, Robert Day, Brynn Levy, Ilene Fennoy, Beatrice Dubern, Christine Poitou, Karine Clement, Merlin G. Butler, Michael Rosenbaum, Jean Pierre Salles, Maithe Tauber, Daniel J. Driscoll, Dieter Egli, and Rudolph L. Leibel http://jci.me.org/88648
Related CommentaryImpaired prohormone processing: a grand unified theory for features of Prader-Willi syndrome?Joseph Polex-Wolf, Giles S.H. Yeo, and Stephen O’Rahilly http://jci.me.org/91307
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JCI | Research: Editor’s picks
Hippo signaling suppresses liver tumor formation through distinct molecular networksThe pathways that control cell proliferation and survival in the liver are tightly regulated, and mutations in multiple pathways have been linked to the development of hepatocellular carcinoma (HCC). Understanding how these pathways prevent tumor initia-tion in normal cells is a key step to improving the prevention and treatment of HCC. Work by Wantae Kim and colleagues determined that Hippo signaling interacts with STAT3, Wnt/β-catenin, and Notch signaling to produce pathway-distinct effects on liver tumor formation. Deletion of the mammalian Hippo kinases Mst1 and Mst2 in mouse livers led to the formation of a positive feedback loop between Notch and Yes-associated protein/tafazzin (YAP/TAZ), which promoted tumor initiation. Wnt/β-catenin signaling repressed tumor progression through these pathways by inhibiting Notch signaling (see the accompanying image). In contrast, STAT3 activation was not required for tumor formation in the absence of MST1/2. These findings provide important insights into how Hippo signaling interacts with distinct mutations to suppress or promote HCC formation.
Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesisWantae Kim, Sanjoy Kumar Khan, Jelena Gvozdenovic-Jeremic, Youngeun Kim, Jason Dahlman, Hanjun Kim, Ogyi Park, Tohru Ishitani, Eek-hoon Jho, Bin Gao, and Yingzi Yang http://jci.me/88486
oncology
Metformin regulates aberrant mitochondrial metabolism in Li-Fraumeni syndrome
Inhibiting integrin α5β1 mitigates hyperresponsiveness in allergic airway contractionWhile preventive immune strategies can help to control asthma, there is still a pressing need for therapeutics to treat airway constriction during acute asthmatic responses. Prior work suggests that mast cell chymase and its murine ortholog mMCP-4 can inhibit tracheal ring contraction, and a deeper understanding of chymase-associated pathways may identify targets for treating airway hyperresponsiveness in asthma. Aparna Sundaram and coworkers examined the mechanisms by which chymase regulates the response of human bronchial rings to cytokine treatment. They determined that chymase cleaves the matrix protein fibronectin, inhibiting cellular adhesion in smooth muscle cells. Integrin α5β1 was the essential mediator of fibronectin-mediated adhesion, and inhibitors of α5β1 reduced allergen-induced bronchoconstric-tion and functioned synergistically with β-adrenergic agonists. This work suggests that α5β1 is a potential target for treating airway hyperresponsiveness in severe asthma.
Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthmaAparna Sundaram, Chun Chen, Amin Khalifeh-Soltani, Amha Atakilit, Xin Ren, Wenli Qiu, Hyunil Jo, William DeGrado, Xiaozhu Huang, and Dean Sheppard http://jci.me/88555
Li-Fraumeni syndrome (LFS) is an inherited disorder associated with increased predisposition to a number of cancers. LFS patients have germline mutations in the gene encoding p53 that increase mitochondrial respiration, but it is unclear whether alterations in mitochondrial metabolism influence tumorigenesis. Ping-yuan Wang, Jie Li, and colleagues observed that metformin treatment inhibited mitochondrial function in a mouse model
of LFS, resulting in decreased tumor formation and increased survival time. Moreover, in a pilot study, treating LFS patients with metformin led to similar inhibition of mitochondrial metabolism and activation of antiproliferation signaling. The finding that metformin, an FDA-approved diabetes medication, can ameliorate aberrant mitochondrial metabolism suggests that it has potential as a cancer prevention strategy in LFS patients.
Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndromePing-yuan Wang, Jie Li, Farzana L. Walcott, Ju-Gyeong Kang, Matthew F. Starost, S. Lalith Talagala, Jie Zhuang, Ji-Hoon Park, Rebecca D. Huffstutler, Christina M. Bryla, Phuong L. Mai, Michael Pollak, Christina M. Annunziata, Sharon A. Savage, Antonio Tito Fojo, and Paul M. Hwang http://jci.me/88668
muscle biology
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JCI | Research: Editor’s picks
Longer red blood cell storage linked to worse transfusion outcomesConcerns about the risks of prolonged red blood cell storage have led to policy changes in some countries that limit storage to five weeks or less prior to transfusion. However, in the United States, current policies allow red cells to be stored for up to six weeks. In a clinical trial, Francesca Rapido and colleagues examined the outcomes of autologous transfusions into healthy volunteers after storage durations of one to six weeks. Participants who received transfusions of red cells that had been stored for six weeks displayed increased signs of extravascular hemolysis compared with patients receiving cells stored for one to five weeks. In the accompanying Commentary, Janet Lee and Daniel Kim-Shapiro discuss the need to further evaluate harmful outcomes of stored blood transfusion and the case for limiting the maximal storage period for red cells to five weeks or less.
Prolonged red cell storage before transfusion increases extravascular hemolysisFrancesca Rapido, Gary M. Brittenham, Sheila Bandyopadhyay, Francesca La Carpia, Camilla L’Acqua, Donald J. McMahon, Abdelhadi Rebbaa, Boguslaw S. Wojczyk, Jane Netterwald, Hangli Wang, Joseph Schwartz, Andrew Eisenberger, Mark Soffing, Randy Yeh, Chaitanya Divgi, Yelena Z. Ginzburg, Beth H. Shaz, Sujit Sheth, Richard O. Francis, Steven L. Spitalnik, and Eldad A. Hod http://jci.me/90837
Related Commentary Stored blood: how old is too old?Janet S. Lee and Daniel B. Kim-Shapiro http://jci.me/91309
Phagocytic myofibroblasts clear damage after myocardial infarctionAfter myocardial infarction, oxygen and nutrient shortages kill cardiomyo-cytes, which generate inflammatory responses as they leak cellular contents. Dead cells are rapidly engulfed to limit secondary damage to the affected area, but the processes responsible for engulfment are not fully described. Michio Nakaya and coworkers discovered a population of phagocytic cardiac myofibro-blasts that secrete an epidermal growth factor, MFG-E8, to promote engulfment of dead cardiomyocytes in a mouse model of myocardial infarction (see the accompanying image). Increased accumulation of dead cardiomyocytes and inflammatory responses observed in MFG-E8–deficient mice were associated with reduced survival after cardiac infarction. These findings identify MFG-E8 as a potential therapeutic target for improving recovery after myocardial infarction.
Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarctionMichio Nakaya, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono, Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, and Hitoshi Kurose http://jci.me/83822
cardiology hematology
Differential inflammatory responses underlie sex disparity in cardiovascular functionSubstantial differences in cardiovascular disease incidence between men and premenopausal women have been attributed to the cardioprotective effect of ovarian hormones, particularly estrogen. Although inflammation exacerbates the development of cardiovascular disease, the molecular pathways contributing to sex-based differences in inflammatory responses are not fully described. Two clinical studies performed by Krishnaraj Rathod and colleagues evaluated inflammation and vascular function in healthy men and women after induction of systemic or localized inflammation. In the first study, they observed that inflammatory and vascular responses in female subjects were less sensitive to the effects of typhoid vaccine–induced systemic inflammation than male subjects. In the second study,
cantharidin-induced blisters resolved more quickly in female subjects, which was associated with enhancement of the D-resolvin pathway. The authors proposed that accelerated resolution of inflammation in women contrib-utes, at least in part, to sex differences in cardiovascular function.
Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humansKrishnaraj S. Rathod, Vikas Kapil, Shanti Velmurugan, Rayomand S. Khambata, Umme Siddique, Saima Khan, Sven Van Eijl, Lorna C. Gee, Jascharanpreet Bansal, Kavi Pitrola, Christopher Shaw, Fulvio D’Acquisto, Romain A. Colas, Federica Marelli-Berg, Jesmond Dalli, and Amrita Ahluwalia http://jci.me.org/89429
vascular biology
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JCI | Research: Editor’s picks
Targeting MyD88 signaling prevents fibrotic responses to kidney injuryFibrotic disease can develop in any tissue, often in response to toxic or ischemic tissue injury. In the fibrotic kidney, a large number of myofibroblasts derive from pericytes. Irina Leaf and coworkers investi-gated a dominant innate immune program activated in human kidney injury and discovered that it is activated predominantly in pericytes. A central node in this program is the myeloid differentiation response protein MyD88. Unexpectedly, they found that MyD88 controls both innate immune and fibrogenic responses in pericytes. Ablating MyD88 or blocking its downstream signaling using a novel inhibitor of IRAK4 protected against fibrotic responses in a mouse model of kidney injury and preserved organ function (see the accompanying image). Targeting MyD88-dependent pathways is a promising approach to preventing fibrotic and inflammatory responses to injury.
High-maintenance β cell identity requires continuous gene activation and suppressionRecent evidence indicates that adverse metabolic conditions can compromise the differentiated state of insulin-producing β cells, but the mechanisms that sustain adult β cell identity and function are not completely described. This month in the JCI, three studies describe how transcription factors that influence β cell development also act to maintain adult β cell identity. Avital Swisa and colleagues found that expression of PAX6 is downregulated in diabetic mice and is central to activating β cell–specific genes and repressing genes typical of other islet cell types, including the fetal hormone ghrelin. A second study, by Benjamin Ediger and coworkers, determined that LIM domain–binding protein 1 (LDB1) also maintains the differentiated state of mature β cells by promoting the expression of genes associated with β cell identity and inhibiting non–β cell gene programs. Finally, work by Giselle Domínguez Gutiérrez and labmates showed that the developmental regulatory factor NK2 homeobox 2 (NKX2.2) continuously suppresses non–β cell genetic programs to maintain adult β cell identity and function. In the absence of NKX2.2, β cells acquired features of other endocrine cell types (see the associated image). In the accompany-ing Commentary, Peter Thompson and Anil Bhushan highlight the tenuous nature of β cell differentiation and emphasize the concept that plasticity in β cell identity and function forms the basis for defective insulin secretion in diabetes and other disorders.
Related ResearchPAX6 maintains β cell identity by repressing genes of alternative islet cell typesAvital Swisa, Dana Avrahami, Noa Eden, Jia Zhang, Eseye Feleke, Tehila Dahan, Yamit Cohen-Tayar, Miri Stolovich-Rain, Klaus H. Kaestner, Benjamin Glaser, Ruth Ashery-Padan, and Yuval Dor http://jci.me/88015
LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cellsBenjamin N. Ediger, Hee-Woong Lim, Christine Juliana, David N. Groff, LaQueena T. Williams, Giselle Dominguez, Jin-Hua Liu, Brandon L. Taylor, Erik R. Walp, Vasumathi Kameswaran, Juxiang Yang, Chengyang Liu, Chad S. Hunter, Klaus H. Kaestner, Ali Naji, Changhong Li, Maike Sander, Roland Stein, Lori Sussel, Kyoung-Jae Won, Catherine Lee May, and Doris A. Stoffers http://jci.me/88016
Pancreatic β cell identity requires continual repression of non–β cell programsGiselle Domínguez Gutiérrez, Aaron S. Bender, Vincenzo Cirulli, Teresa L. Mastracci,
Stephen M. Kelly, Aristotelis Tsirigos, Klaus H. Kaestner, and Lori Sussel http://jci.me/88017
Related Commentaryβ Cells led astray by transcription factors and the company they keepPeter Thompson and Anil Bhushan http://jci.me/91304
metabolism
inflammation
Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injuryIrina A. Leaf, Shunsaku Nakagawa, Bryce G. Johnson, Jin Joo Cha, Kristen Mittelsteadt, Kevin M. Guckian, Ivan G. Gomez, William A. Altemeier, and Jeremy S. Duffield http://jci.me/87532
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JCI | Research: Editor’s picks
neuroscience
aids/hiv
Interfering with interferon type I signaling boosts HIV-1 suppressionAlthough combined antiretroviral therapy (cART) can effectively suppress HIV-1 replication, some HIV-1–positive individuals still experience chronic immune activation and exhaustion that can accelerate disease progression. This chronic immune activation has been linked to persistent interferon type I (IFN-I) signaling. Now, two studies have demonstrated that blocking IFN-I signaling can augment cART efficacy in humanized mouse models of HIV-1 infection. Anjie Zhen and labmates treated HIV-1–infected mice with an antibody to block human IFN receptor 2 and observed reduced signs of T cell exhaustion and viral load. Liang Cheng and Jianping Ma developed an antibody to target the human IFN-α/β receptor, which reversed immune hyperactivation in the mouse model. In
Microglial TGF-β1 mediates repair and recovery after intracerebral hemorrhageIntracerebral hemorrhage (ICH) and other acute brain injuries cause rapid inflammatory responses in the brain that activate resident microglia and immune responses. These inflammatory and immune responses contribute to risk of secondary injury after ICH. Roslyn Taylor and labmates examined the activation profile of microglia in the early proinflammatory and later resolution phases of inflammation in a mouse model of ICH. They determined that the resolution phase of inflammation coincides with increases in TGF-β1 pathway activation in microglia (see the accompanying image). Treating mice with TGF-β1 immediately after ICH improved motor function. Further, they found that patients who displayed early increases in plasma TGF-β1 experienced better outcomes 3 months after the ICH episode. Together, these results indicated that activation of the TGF-β1 pathway mitigates microglia-mediated inflammation after injury, pointing to TGF-β1 treatment as a potential approach for preventing further damage after acute brain injury.
TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhageRoslyn A. Taylor, Che-Feng Chang, Brittany A. Goods, Matthew D. Hammond, Brian Mac Grory, Youxi Ai, Arthur F. Steinschneider, Stephen C. Renfroe, Michael H. Askenase, Louise D. McCullough, Scott E. Kasner, Michael T. Mullen, David A. Hafler, J. Christopher Love, and Lauren H. Sansing http://jci.me.org/88647
both studies, blockade of IFN-I signaling synergized with cART treatment in HIV-1–infected mice, leading to enhanced T cell responses and lower viral load. In the accompanying Commen-tary, Steven Deeks, Pamela Odorizzi, and Rafick Sekaly suggest that further evaluation of IFN-I blockade as a supplement to cART is warranted.
Related ResearchTargeting type I interferon–mediated activation restores immune function in chronic HIV infectionAnjie Zhen, Valerie Rezek, Cindy Youn, Brianna Lam, Nelson Chang, Jonathan Rick, Mayra Carrillo, Heather Martin, Saro Kasparian, Philip Syed, Nicholas Rice, David G. Brooks, and Scott G. Kitchen http://jci.me/89488
Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirsLiang Cheng, Jianping Ma, Jingyun Li, Dan Li, Guangming Li, Feng Li, Qing Zhang, Haisheng Yu, Fumihiko Yasui, Chaobaihui Ye, Li-Chung Tsao, Zhiyuan Hu, Lishan Su, and Liguo Zhang http://jci.me/90745
Related CommentaryThe interferon paradox: can inhibiting an antiviral mechanism advance an HIV cure?Steven G. Deeks, Pamela M. Odorizzi, and Rafick-Pierre Sekaly http://jci.me/91916
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JCI | Features
conversations with giants in medicine
Bruce AlbertsThough Bruce Alberts is well known for his work on the biochemistry of DNA replication and as the editor-in-chief of Science, he is also recognizable as the author of the seminal biology textbook Molecular Biology of the Cell. Alberts served as the president of the National Academy of Sciences for over a decade and is currently a professor at the University of California, San Francisco. This year, his dedication to advancing science policy and education was recognized with the Lasker-Koshland Special Achievement Award. JCI Editor at Large Ushma Neill sat down with Alberts to talk about how his background in science shaped his later work as an educator and leader in science policy. They also discuss the challenges of improving science education through writing, editing, and policy making. http://jci.me/91072
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JCI Review Series
Metabolism and inflammationSeries Editors: Alan R. Saltiel and Jerrold M. Olefsky
Understanding the interactions between inflammation and metabolic dysfunctionMetabolic syndrome comprises a constellation of conditions including central obesity, glucose intolerance, and dyslipidemia. These conditions enhance the risk of type 2 diabetes, cardiovascular disease, fatty liver/cir-rhosis, hypertension, and cancer. The finding over 20 years ago that the inflammatory mediator TNF-α is overexpressed in adipose tissue funda-mentally changed our understanding of obesity and metabolic syndrome. We now know that metabolic syndrome in humans is characterized by chronic low-grade inflammation in multiple organs, and we are now begin-ning to delineate the mechanisms by which inflammation and metabolism influence each other. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a proinflam-matory phenotype.
Inflammatory mechanisms linking obesity and metabolic diseaseAlan R. Saltiel and Jerrold M. Olefsky http://jci.me/92035
Alan R. Saltiel, PhD, is the Director of the Institute for Diabetes and Metabolic Health at the University of California, San Diego, a member of the National Academy of Medicine, a fellow of the American Asso-ciation for the Advancement of Science, and a recipient of the American Diabetes Association’s Rosalyn Yalow Research and Development Award and the John J. Abel Award from the American Society for Phar-macology and Experimental Therapeutics. His laboratory investigates the molecular events involved in the regulation of glucose uptake and storage, with a focus on the mechanisms that underlie the action of insulin and the links between obesity and diabetes.
Jerrold M. Olefsky, MD, is Associate Dean for Scientific Affairs and Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism in the Department of Medicine at the University of California, San Diego, and a recipient of the American Diabetes Association’s Banting Medal for Scientific Achievement. His laboratory investigates the molecular mechanisms of insulin and growth factor action in multiple tissues, with an emphasis on the insulin signaling pathway that stimulates glucose transport.
Role of innate and adaptive immunity in obesity-associated metabolic diseaseTracey McLaughlin, Shelley E. Ackerman, Lei Shen, and Edgar Engleman http://jci.me/88876
Islet inflammation in type 2 diabetes and physiologyKosei Eguchi and Ryozo Nagai http://jci.me/88877
Hypothalamic inflammation in obesity and metabolic diseaseAlexander Jais and Jens C. Brüning http://jci.me/88878
Immunologic impact of the intestine in metabolic diseaseDaniel A. Winer, Shawn Winer, Helen J. Dranse, and Tony K.T. Lam http://jci.me/88879
Skeletal muscle inflammation and insulin resistance in obesityHuaizhu Wu and Christie M. Ballantyne http://jci.me/88880
Liver inflammation and fibrosisYukinori Koyama and David A. Brenner http://jci.me/88881
The initiation of metabolic inflammation in childhood obesityKanakadurga Singer and Carey N. Lumeng http://jci.me/88882
The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesisClair Crewe, Yu Aaron An, and Philipp E. Scherer http://jci.me/88883
Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular riskAllison B. Goldfine and Steven E. Shoelson http://jci.me/88884
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aids/hivTargeting type I interferon–mediated activation restores immune function in chronic HIV infection p. 6Anjie Zhen, Valerie Rezek, Cindy Youn, Brianna Lam, Nelson Chang, Jonathan Rick, Mayra Carrillo, Heather Martin, Saro Kasparian, Philip Syed, Nicholas Rice, David G. Brooks, and Scott G. Kitchen http://jci.me/89488
Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs p. 6Liang Cheng, Jianping Ma, Jingyun Li, Dan Li, Guangming Li, Feng Li, Qing Zhang, Haisheng Yu, Fumihiko Yasui, Chaobaihui Ye, Li-Chung Tsao, Zhiyuan Hu, Lishan Su, and Liguo Zhang http://jci.me/90745
cardiologyCardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction p. 4Michio Nakaya, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono, Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, and Hitoshi Kurose http://jci.me/83822
The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophyBernard Thienpont, Jan Magnus Aronsen, Emma Louise Robinson, Hanneke Okkenhaug, Elena Loche, Arianna Ferrini, Patrick Brien, Kanar Alkass, Antonio Tomasso, Asmita Agrawal, Olaf Bergmann, Ivar Sjaastad, Wolf Reik, and Hywel Llewelyn Roderick http://jci.me/88353
cell biologyEpithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11 p. 1Xiaochao Tan, Priyam Banerjee, Hou-Fu Guo, Stephen Ireland, Daniela Pankova, Young-ho Ahn, Irodotos Michail Nikolaidis, Xin Liu, Yanbin Zhao, Yongming Xue, Alan R. Burns, Jonathon Roybal, Don L. Gibbons, Tomasz Zal, Chad J. Creighton, Daniel Ungar, Yanzhuang Wang, and Jonathan M. Kurie http://jci.me/88736
dermatologyTuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activationJuxiang Cao, Magdalena E. Tyburczy, Joel Moss, Thomas N. Darling, Hans R. Widlund, and David J. Kwiatkowski http://jci.me/84262
Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapyTrevor J. Cunningham, Mary Tabacchi, Jean-Pierre Eliane, Sara Moradi Tuchayi, Sindhu Manivasagam, Hengameh Mirzaalian, Ahu Turkoz, Raphael Kopan, Andras Schaffer, Arturo P. Saavedra, Michael Wallendorf, Lynn A. Cornelius, and Shadmehr Demehri http://jci.me/89820
endocrinologyDeficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome p. 2Lisa C. Burnett, Charles A. LeDuc, Carlos R. Sulsona, Daniel Paull, Richard Rausch, Sanaa Eddiry, Jayne F. Martin Carli, Michael V. Morabito, Alicja A. Skowronski, Gabriela Hubner, Matthew Zimmer, Liheng Wang, Robert Day, Brynn Levy, Ilene Fennoy, Beatrice Dubern, Christine Poitou, Karine Clement, Merlin G. Butler, Michael Rosenbaum, Jean Pierre Salles, Maithe Tauber, Daniel J. Driscoll, Dieter Egli, and Rudolph L. Leibel http://jci.me/88648
Current research articles
Actinic keratosis
Cardiac myofibroblast engulfment
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hematologyProlonged red cell storage before transfusion increases extravascular hemolysis p. 4Francesca Rapido, Gary M. Brittenham, Sheila Bandyopadhyay, Francesca La Carpia, Camilla L’Acqua, Donald J. McMahon, Abdelhadi Rebbaa, Boguslaw S. Wojczyk, Jane Netterwald, Hangli Wang, Joseph Schwartz, Andrew Eisenberger, Mark Soffing, Randy Yeh, Chaitanya Divgi, Yelena Z. Ginzburg, Beth H. Shaz, Sujit Sheth, Richard O. Francis, Steven L. Spitalnik, and Eldad A. Hod http://jci.me/90837
immunologyBiallelic mutations in IRF8 impair human NK cell maturation and functionEmily M. Mace, Venetia Bigley, Justin T. Gunesch, Ivan K. Chinn, Laura S. Angelo, Matthew A. Care, Sheetal Maisuria, Michael D. Keller, Sumihito Togi, Levi B. Watkin, David F. LaRosa, Shalini N. Jhangiani, Donna M. Muzny, Asbjørg Stray-Pedersen, Zeynep Coban Akdemir, Jansen B. Smith, Mayra Hernández-Sanabria, Duy T. Le, Graham D. Hogg, Tram N. Cao, Aharon G. Freud, Eva P. Szymanski, Sinisa Savic, Matthew Collin, Andrew J. Cant, Richard A. Gibbs, Steven M. Holland, Michael A. Caligiuri, Keiko Ozato, Silke Paust, Gina M. Doody, James R. Lupski, and Jordan S. Orange http://jci.me/86276
inflammationPericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury p. 5Irina A. Leaf, Shunsaku Nakagawa, Bryce G. Johnson, Jin Joo Cha, Kristen Mittelsteadt, Kevin M. Guckian, Ivan G. Gomez, William A. Altemeier, and Jeremy S. Duffield http://jci.me/87532
metabolismPAX6 maintains β cell identity by repressing genes of alternative islet cell types p. 5Avital Swisa, Dana Avrahami, Noa Eden, Jia Zhang, Eseye Feleke, Tehila Dahan, Yamit Cohen-Tayar, Miri Stolovich-Rain, Klaus H. Kaestner, Benjamin Glaser, Ruth Ashery-Padan, and Yuval Dor http://jci.me/88015
LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cells p. 5Benjamin N. Ediger, Hee-Woong Lim, Christine Juliana, David N. Groff, LaQueena T. Williams, Giselle Dominguez, Jin-Hua Liu, Brandon L. Taylor, Erik R. Walp, Vasumathi Kameswaran, Juxiang Yang, Chengyang Liu, Chad S. Hunter, Klaus H. Kaestner, Ali Naji, Changhong Li, Maike Sander, Roland Stein, Lori Sussel, Kyoung-Jae Won, Catherine Lee May, and Doris A. Stoffers http://jci.me/88016
Pancreatic β cell identity requires continual repression of non–β cell programs p. 5Giselle Domínguez Gutiérrez, Aaron S. Bender, Vincenzo Cirulli, Teresa L. Mastracci, Stephen M. Kelly, Aristotelis Tsirigos, Klaus H. Kaestner, and Lori Sussel http://jci.me/88017
muscle biologyTargeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma p. 3Aparna Sundaram, Chun Chen, Amin Khalifeh-Soltani, Amha Atakilit, Xin Ren, Wenli Qiu, Hyunil Jo, William DeGrado, Xiaozhu Huang, and Dean Sheppard http://jci.me/88555
Current research articles
Pericyte inflammation
Pancreatic islet
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nephrologyVEGF regulates local inhibitory complement proteins in the eye and kidney p. 2Lindsay S. Keir, Rachel Firth, Lyndsey Aponik, Daniel Feitelberg, Susumu Sakimoto, Edith Aguilar, Gavin I. Welsh, Anna Richards, Yoshihiko Usui, Simon C. Satchell, Valeryia Kuzmuk, Richard J. Coward, Jonathan Goult, Katherine R. Bull, Ruchi Sharma, Kapil Bharti, Peter D. Westenskow, Iacovos P. Michael, Moin A. Saleem, and Martin Friedlander http://jci.me/86418
neuroscienceTGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage p. 6Roslyn A. Taylor, Che-Feng Chang, Brittany A. Goods, Matthew D. Hammond, Brian Mac Grory, Youxi Ai, Arthur F. Steinschneider, Stephen C. Renfroe, Michael H. Askenase, Louise D. McCullough, Scott E. Kasner, Michael T. Mullen, David A. Hafler, J. Christopher Love, and Lauren H. Sansing http://jci.me/88647
oncologyDual modulation of MCL-1 and mTOR determines the response to sunitinibMohamed Elgendy, Amal Kamal Abdel-Aziz, Salvatore Lorenzo Renne, Viviana Bornaghi, Giuseppe Procopio, Maurizio Colecchia, Ravindran Kanesvaran, Chee Keong Toh, Daniela Bossi, Isabella Pallavicini, Jose Luis Perez-Gracia, Maria Dolores Lozano, Valeria Giandomenico, Ciro Mercurio, Luisa Lanfrancone, Nicola Fazio, Franco Nole, Bin Tean Teh, Giuseppe Renne, and Saverio Minucci http://jci.me/84386
Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis p. 3Wantae Kim, Sanjoy Kumar Khan, Jelena Gvozdenovic-Jeremic, Youngeun Kim, Jason Dahlman, Hanjun Kim, Ogyi Park, Tohru Ishitani, Eek-hoon Jho, Bin Gao, and Yingzi Yang http://jci.me/88486
Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome p. 3Ping-yuan Wang, Jie Li, Farzana L. Walcott, Ju-Gyeong Kang, Matthew F. Starost, S. Lalith Talagala, Jie Zhuang, Ji-Hoon Park, Rebecca D. Huffstutler, Christina M. Brylan, Phuong L. Mai, Michael Pollak, Christina M. Annuziata, Sharon A. Savage, Antonio Tito Fojo, and Paul M. Hwang http://jci.me/88668
Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapiesMihalis S. Kariolis, Yu Rebecca Miao, Anh Diep, Shannon E. Nash, Monica M. Olcina, Dadi Jiang, Douglas S. Jones II, Shiven Kapur, Irimpan I. Mathews, Albert C. Koong, Erinn B. Rankin, Jennifer R. Cochran, and Amato J. Giaccia http://jci.me/85610
vascular biologyAccelerated resolution of inflammation underlies sex differences in inflammatory responses in humans p. 4Krishnaraj S. Rathod, Vikas Kapil, Shanti Velmurugan, Rayomand S. Khambata, Umme Siddique, Saima Khan, Sven Van Eijl, Lorna C. Gee, Jascharanpreet Bansal, Kavi Pitrola, Christopher Shaw, Fulvio D’Acquisto, Romain A. Colas, Federica Marelli-Berg, Jesmond Dalli, and Amrita Ahluwalia http://jci.me/89429
Complement in kidney
DNA damage
Liver tumorigenesis
HCT116 xenograft
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JCI Insight is a new peer-reviewed journal dedicated to biomedical research, ranging from preclinical to clinical studies.More information: http://jci.me/insinf or [email protected]
Editor’s picks
hepatology
A critical role for HDL/sphingosine-1-phosphate receptor-1 signaling after liver injuryLiver injury is a leading cause of morbidity and mortality, but could potentially be treated with strategies to stimulate liver regeneration. Disruption of the crosstalk between hepatocytes and the liver sinusoidal vascular endothelium leads to impaired regeneration and maladaptive healing characterized by fibrosis. Using three murine models of liver regeneration and repair, Bi-Sen Ding and colleagues show that endothelial sphingosine-1-phosphate (S1P) bound to HDL (HDL-S1P) induces liver regeneration and attenuates fibrosis. After a partial hepatectomy, mice lacking HDL-S1P exhibited impaired regeneration, aberrant vascular remodeling, thrombosis, and perisinusoidal fibrosis (see the accompanying image). Conversely, elevation of plasma HDL-S1P levels or treatment with an S1P receptor-1 (S1P1) agonist enhanced liver regeneration. These findings suggest that therapeutic strategies to stimulate S1P1 signaling may ameliorate liver fibrosis.
HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liverBi-Sen Ding, Catherine H. Liu, Yue Sun, Yutian Chen, Steven L. Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R. Schwab, Shahin Rafii, and Timothy Hla http://jci.me/87058
The β-adrenergic receptor mediates hypoxia sensing
vascular biology
demonstrate that β-ARs mediate molecular and physiological responses to hypoxia.
Hypoxia sensing through β-adrenergic receptorsHoi I. Cheong, Kewal Asosingh, Olivia R. Stephens, Kimberly A. Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R. Stark, Sathyamangla V. Naga Prasad, and Serpil C. Erzurum http://jci.me/90240
Tissue hypoxia induces a series of adaptive responses through the hypoxia-induced transcrip-tion factor HIF-1α to increase red blood cells and generate new blood vessels; however, the molecular mechanisms by which cells sense hypoxia are not entirely clear. Hoi Cheong and colleagues hypoth-esized that the β-adrenergic receptor (β-AR) mediates hypoxia sensing and is necessary for HIF-1α accumulation. They found that treatment of mice with a β-AR antagonist (beta blocker) impaired hypoxia-induced HIF-1α accumulation in
the kidney and attenuated erythropoietin production and erythropoiesis. Beta blocker treatment of human endothelial cells also impaired hypoxia-induced HIF-1α accumulation and downstream gene regulation. Mechanistically, Cheong and colleagues showed that hypoxia induces changes in phosphorylation of a specific set of residues on β-ARs under hypoxic conditions; mutation of GPCR kinase (GRK) phosphorylation sites or inhibition of GRK abrogated hypoxia-induced HIF-1α accumulation. These studies
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JCI Insight | Editor’s picks
clinical medicine
oncology
Tracking changes in tumor-infiltrating lymphocyte behavior
Early immunological changes in human liver transplant ischemia/reperfusion injuryOrthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. Ischemia/reperfusion injury (IRI) can compromise allograft survival; however, our understanding of the underlying immunological mechanisms is limited. Rebecca Sosa and colleagues conducted a longitudinal study in 53 OLT patients to measure the expression of 38 cytokines, chemokines, and growth factors in the circulating systemic blood before and after transplant and in the portal blood before and after reperfusion, as well as the expression of cytokine receptor genes in donor allograft biopsies before and after transplant. They then analyzed the relationship between cytokine expression and standard clinical liver function tests after transplant and biopsy-proven IRI (see the accompanying image). They identified 14 cytokines that were increased in the systemic or portal blood of patients with biopsy-proven IRI and expression of 10 cognate receptors for these cytokines in the donor organs. These findings will help to identify immunological mechanisms that underlie IRI and may be useful in identifying at-risk patients.
Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantationRebecca A. Sosa, Ali Zarrinpar, Maura Rossetti, Charles R. Lassman, Bita V. Naini, Nakul Datta, Ping Rao, Nicholas Harre, Ying Zheng, Roberto Spreafico, Alexander Hoffmann, Ronald W. Busuttil, David W. Gjertson, Yuan Zhai, Jerzy W. Kupiec-Weglinski, and Elaine F. Reed http://jci.me/89679
Signals within the tumor microenvironment tolerize the tumor-infiltrating lymphocytes (TILs), making them unable to eliminate the tumor. Tolerized TILs express elevated levels of exhaustion markers such as inhibitory receptors and are unable to make effector cytokines, but the timing and sequence of events in this tolerization process are unclear. Bijan Boldajipour and colleagues used high-resolution intravital imaging to track the behavior of TILs in an autochthonus murine model of breast cancer to
understand the relationship between cellular behavior and tolerization. They found that TIL behavior began to change within the first few days of tumor residence when TILs arrested on tumor-associ-ated macrophages. Within 10 days, the cells became motile, but T cell receptor signaling appeared to be absent. Unexpectedly, many of these cells underwent active cell division (see the accompanying image), which was at least partially reliant on IL-15. These data indicate that TILs undergo sequential
reprogramming by the tumor microenvironment that renders them antigen insensitive and maintains them in a dysfunctional state.
Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokineBijan Boldajipour, Amanda Nelson, and Matthew F. Krummel http://jci.me/89289
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JCI Insight | Editor’s picks
pulmonology
Due to the increasing evidence that the respiratory epithelium plays a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), Yan Xu, Takako Mizuno, and colleagues performed single-cell RNA sequencing in epithelial cells isolated from the lungs of IPF patients and healthy controls to identify disease-relevant processes. Compared with normal lung epithelial cells, which were characterized as highly differentiated alveolar type 2 cells, IPF epithelial cells could be divided into three distinct subsets that included airway basal and goblet cells and an atypical transitional cell. Further, many IPF epithelial cells exhibited indeterminate states of differentiation that were not observed in normal lung (see
the accompanying image). Moreover, several signaling pathways were aberrantly activated in IPF epithelium, including TGF-β, HIPPO/YAP, p53, WNT, and AKT/PI3K. These data identify processes and pathways that may underlie IPF pathology.
Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosisYan Xu, Takako Mizuno, Anusha Sridharan, Yina Du, Minzhe Guo, Jie Tang, Kathryn A. Wikenheiser-Brokamp, Anne-Karina T. Perl, Vincent A. Funari, Jason J. Gokey, Barry R. Stripp, and Jeffrey A. Whitsett http://jci.me.org/90558
Single-cell RNA sequencing identifies epithelial alterations in idiopathic pulmonary fibrosis
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Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic diseaseNaoki Nakagawa, Luke Barron, Ivan G. Gomez, Bryce G. Johnson, Allie M. Roach, Sei Kameoka, Richard M. Jack, Mark L. Lupher Jr., Sina A. Gharib, and Jeremy S. Duffield http://jci.me/87446
B cell repertoire expansion occurs in meningeal ectopic lymphoid tissueKlaus Lehmann-Horn, Sheng-zhi Wang, Sharon A. Sagan, Scott S. Zamvil, and H.-Christian von Büdingen http://jci.me/87234
IFN-ε protects primary macrophages against HIV infectionCarley Tasker, Selvakumar Subbian, Pan Gao, Jennifer Couret, Carly Levine, Saleena Ghanny, Patricia Soteropoulos, Xilin Zhao, Nathaniel Landau, Wuyuan Lu, and Theresa L. Chang http://jci.me/88255
Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaquesKan Luo, Hua-Xin Liao, Ruijun Zhang, David Easterhoff, Kevin Wiehe, Thaddeus C. Gurley, Lawrence C. Armand, Ashley A. Allen, Tarra A. Von Holle, Dawn J. Marshall, John F. Whitesides, Jamie Pritchett, Andrew Foulger, Giovanna Hernandez, Robert Parks, Krissey E. Lloyd, Christina Stolarchuk, Sheetal Sawant, Jessica Peel, Nicole L. Yates, Erika Dunford, Sabrina Arora, Amy Wang, Cindy M. Bowman, Laura L. Sutherland, Richard M. Scearce, Shi-Mao Xia, Mattia Bonsignori, Justin Pollara, R. Whitney Edwards, Sampa Santra, Norman L. Letvin, James Tartaglia, Donald Francis, Faruk Sinangil, Carter Lee, Jaranit Kaewkungwal, Sorachai Nitayaphan, Punnee Pitisuttithum, Supachai Rerks-Ngarm, Nelson L. Michael, Jerome H. Kim, S. Munir Alam, Nathan A. Vandergrift, Guido Ferrari, David C. Montefiori, Georgia D. Tomaras, Barton F. Haynes, and. M. Anthony Moody http://jci.me/88522
Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetesHoward R. Seay, Erik Yusko, Stephanie J. Rothweiler, Lin Zhang, Amanda L. Posgai, Martha Campbell-Thompson, Marissa Vignali, Ryan O. Emerson, John S. Kaddis, Dave Ko, Maki Nakayama, Mia J. Smith, John C. Cambier, Alberto Pugliese, Mark A. Atkinson, Harlan S. Robins, and Todd M. Brusko http://jci.me/88242
Chorioretinal thinning in chronic kidney disease links to inflammation and endothelial dysfunctionCraig Balmforth, Job J.M.H. van Bragt, Titia Ruijs, James R. Cameron, Robert Kimmitt, Rebecca Moorhouse, Alicja Czopek, May Khei Hu, Peter J. Gallacher, James W. Dear, Shyamanga Borooah, Iain M. MacIntyre, Tom M.C. Pearson, Laura Willox, Dinesh Talwar, Muriel Tafflet, Christophe Roubeix, Florian Sennlaub, Siddharthan Chandran, Baljean Dhillon, David J. Webb, and Neeraj Dhaun http://jci.me/89173
Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine p. 13Bijan Boldajipour, Amanda Nelson, and Matthew F. Krummel http://jci.me/89289
IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humansFawaz Alzaid, Floriane Lagadec, Miguel Albuquerque, Raphaëlle Ballaire, Lucie Orliaguet, Isabelle Hainault, Corinne Blugeon, Sophie Lemoine, Agnès Lehuen, David G. Saliba, Irina A. Udalova, Valérie Paradis, Fabienne Foufelle, and Nicolas Venteclef http://jci.me/88689
Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation p. 13Rebecca A. Sosa, Ali Zarrinpar, Maura Rossetti, Charles R. Lassman, Bita V. Naini, Nakul Datta, Ping Rao, Nicholas Harre, Ying Zheng, Roberto Spreafico, Alexander Hoffmann, Ronald W. Busuttil, David W. Gjertson, Yuan Zhai, Jerzy W. Kupiec-Weglinski, and Elaine F. Reed http://jci.me/89679
Hepatic fibrosis
Pancreatic islet lymphocytes
Kidney fibrosis
Current research articles
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mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regenerationShailesh Agarwal, David Cholok, Shawn Loder, John Li, Christopher Breuler, Michael T. Chung, Hsiao Hsin Sung, Kavitha Ranganathan, Joseph Habbouche, James Drake, Joshua Peterson, Caitlin Priest, Shuli Li, Yuji Mishina, and Benjamin Levi http://jci.me/89805
Interleukin 6 regulates psoriasiform inflammation–associated thrombosisYunmei Wang, Jackelyn B. Golden, Yi Fritz, Xiufen Zhang, Doina Diaconu, Maya I. Camhi, Huiyun Gao, Sean M. Dawes, Xianying Xing, Santhi K. Ganesh, Johann E. Gudjonsson, Daniel I. Simon, Thomas S. McCormick, and Nicole L. Ward http://jci.me/89384
DNA methylation in lung cells is associated with asthma endotypes and genetic riskJessie Nicodemus-Johnson, Rachel A. Myers, Noburu J. Sakabe, Debora R. Sobreira, Douglas K. Hogarth, Edward T. Naureckas, Anne I. Sperling, Julian Solway, Steven R. White, Marcelo A. Nobrega, Dan L. Nicolae, Yoav Gilad, and Carole Ober http://jci.me/90151
Low-dose dasatinib rescues cardiac function in Noonan syndromeJae-Sung Yi, Yan Huang, Andrea T. Kwaczala, Ivana Y. Kuo, Barbara E. Ehrlich, Stuart G. Campbell, Frank J. Giordano, and Anton M. Bennett http://jci.me/90220
miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathwaysLingyin Ge, David M. Habiel, Phil M. Hansbro, Richard Y. Kim, Sina A. Gharib, Jeffery D. Edelman, Melanie Königshoff, Tanyalak Parimon, Rena Brauer, Ying Huang, Jenieke Allen, Dian Jiang, Adrianne A. Kurkciyan, Takako Mizuno, Barry R. Stripp, Paul W. Noble, Cory M. Hogaboam, and Peter Chen http://jci.me/90301
Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis p. 14Yan Xu, Takako Mizuno, Anusha Sridharan, Yina Du, Minzhe Guo, Jie Tang, Kathryn A. Wikenheiser-Brokamp, Anne-Karina T. Perl, Vincent A. Funari, Jason J. Gokey, Barry R. Stripp, and Jeffrey A. Whitsett http://jci.me/90558
Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitisRyan E. Feaver, Banumathi K. Cole, Mark J. Lawson, Stephen A. Hoang, Svetlana Marukian, Brett R. Blackman, Robert A. Figler, Arun J. Sanyal, Brian R. Wamhoff, and Ajit Dash http://jci.me/90954
ATG16L1 governs placental infection risk and preterm birth in mice and womenBin Cao, Colin Macones, and Indira U. Mysorekar http://jci.me/86654
HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver p. 12Bi-Sen Ding, Catherine H. Liu, Yue Sun, Yutian Chen, Steven L. Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R. Schwab, Shahin Rafii, and Timothy Hla http://jci.me/87058
Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cellsChandra Sekhar Boddupalli, Noffar Bar, Krishna Kadaveru, Michael Krauthammer, Natopol Pornputtapong, Zifeng Mai, Stephan Ariyan, Deepak Narayan, Harriet Kluger, Yanhong Deng, Rakesh Verma, Rituparna Das, Antonella Bacchiocchi, Ruth Halaban, Mario Sznol, Madhav V. Dhodapkar, and Kavita M. Dhodapkar http://jci.me/88955
Psoriasiform inflammation
Lung fibrosis
Biliary epithelial injury
Current research articles
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Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severityShane Lofgren, Monique Hinchcliff, Mary Carns, Tammara Wood, Kathleen Aren, Esperanza Arroyo, Peggie Cheung, Alex Kuo, Antonia Valenzuela, Anna Haemel, Paul J. Wolters, Jessica Gordon, Robert Spiera, Shervin Assassi, Francesco Boin, Lorinda Chung, David Fiorentino, Paul J. Utz, Michael Whitfield, and Purvesh Khatri http://jci.me/89073
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndromeØystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E. Dyrstad, Kine Alme, Ingrid G. Rekeland, Dipak Sapkota, Gro V. Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E. Gotaas, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M. Ueland, Olav Dahl, and Karl J. Tronstad http://jci.me/89376
Inactivation of ABL kinases suppresses non–small cell lung cancer metastasisJing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, and Ann Marie Pendergast http://jci.me/89647
Hypoxia sensing through β-adrenergic receptors p. 12Hoi I. Cheong, Kewal Asosingh, Olivia R. Stephens, Kimberly A. Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R. Stark, Sathyamangla V. Naga Prasad, and Serpil C. Erzurum http://jci.me/90240
Disease modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscleDavid W. Hammers, Margaret M. Sleeper, Sean C. Forbes, Cora C. Coker, Michael R. Jirousek, Michael Zimmer, Glenn A. Walter, and H. Lee Sweeney http://jci.me/90341
Identifying the third dimension in 2D fluoroscopy to create 3D cardiac mapsJasbir Sra, David Krum, Indrajit Choudhuri, Barry Belanger, Mark Palma, Donald Brodnick, and Daniel B. Rowe http://jci.me/90453
Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapyJiha Kim, Pedro Correa de Sampaio, Donna Marie Lundy, Qian Peng, Kurt W. Evans, Hikaru Sugimoto, Mihai Gagea, Yvonne Kienast, Nayra Soares do Amaral, Rafael Malagoli Rocha, Hans P. Eikesdal, Per Eystein Lønning, Funda Meric-Bernstam, and Valerie S. LeBleu http://jci.me/90733
Non–small cell lung carcinoma
NF-κB inhibitor–treated muscle
Intratumoral hypoxia