jci.org/this-month Mucus plugs may worsen airway obstruction in asthma patients 3 LRP1 balances lipid and glucose handling in obesity 4 Hemoglobin-activated macrophages exacerbate atherosclerosis 4 Efficient Staph aggregation promotes lethal lung damage 5 JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight Scan for the digital version of JCI This Month. March 2018 Factor XII does double duty in wound healing p. 2 This Month
Transcript
jci.org/this-month
Mucus plugs may worsen airway obstruction in asthma patients 3
LRP1 balances lipid and glucose handling in obesity 4
Journal of Clinical Investigation Consulting Editors
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j c i . o r g / t h i s - m o n t h m a r c h 2 0 1 8 1
For the JCIEditorGordon F. Tomaselli
Deputy EditorsRexford S. Ahima, Arturo Casadevall
Associate EditorsRichard F. Ambinder, Mark E. Anderson, Mary Y. Armanios, William R. Bishai, Robert A. Brodsky, Peter A. Calabresi, Thomas L. Clemens, Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, Sharon Gerecht, Paul M. Hassoun, Elizabeth M. Jaffe, Mariana J. Kaplan, David A. Kass, Leo Luznik, Kieren A. Marr, Timothy H. Moran, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Stuart C. Ray, Marc L. Reitman, Jeffrey D. Rothstein, Scheherazade Sadegh-Nasseri, Jonathan Schneck, Gregg L. Semenza, Robert F. Siliciano, Charlotte Sumner, Simeon I. Taylor, David L. Thomas, Robert G. Weiss, Sarah J. Wheeler, Marsha Wills-Karp
BiostatisticianEliseo Guallar
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JCI ScholarsJustin Lowenthal, Austin K. Mattox
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JCI This Month ISSN 2324-7703 (print)JCI This Month ISSN 2325-4556 (online)
For the full JCI online: jci.me/128/3
The JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.
Featured Editor
Marsha Wills-Karp, PhD, Associate Edi-tor, is the Anna M. Baetjer Professor and Chair of the Department of Environmental Health and Engineering at the Johns Hop-kins Bloomberg School of Public Health. Her research is focused on understanding the immunogenic basis of allergic diseases, with a specific interest in the immune mechanisms that contribute to asthma pathogenesis. Prior to her current role at Johns Hopkins, Dr. Wills-Karp established and directed the Division of Immunobiology at Cincinnati Children’s Hos-
pital Medical Center. In addition to her contributions to the JCI, she has served as the Deputy Editor of Mucosal Immunology and is a member of the Society for Mucosal Immunology, the American Association of Immunologists, and the American Academy of Allergy, Asthma and Immunology.
Publication highlights
Gour N, Lajoie S, Smole U, White M, Hu D, Goddard P, Huntsman S, Eng C, Mak A, Oh S, Kim J-H, Sharma A, Plante S, Salem H, Resch Y, Xiao X, Yao N, Singh A, Vrtala S, Chakir J, Burchard EG, Lane AP, Wills-Karp M. Dysregulated invertebrate tropomyosin-dectin-1 interactions confer susceptibility to allergic diseases. Sci Immunol. In press.
Eiymo Mwa Mpollo MS, Brandt EB, Shanmukhappa SK, Arumugam PI, Tiwari S, Loberg A, Pillis D, Rizvi T, Lindsey M, Jonck B, Carmeliet P, Kalra VK, Le Cras TD, Ratner N, Wills-Karp M, Hershey GK, Malik P. Placenta growth factor augments airway hyperre-sponsiveness via leukotrienes and IL-13. J Clin Invest. 2016;126(2):571–584.
Nachman RM, Mao G, Zhang X, Hong X, Chen Z, Soria CS, He H, Wang G, Caruso D, Pearson C, Biswal S, Zuckerman B, Wills-Karp M, Wang X. Intrauterine inflammation and maternal exposure to ambient PM2.5 during preconception and specific periods of pregnancy: the Boston Birth Cohort. Environ Health Perspect. 2016;124(10):1608–1615.
Sussan TE, Sudini K, Talbot CC Jr, Wang X, Wills-Karp M, Burd I, Biswal S. Nrf2 regu-lates gene-environment interactions in an animal model of intrauterine inflammation: implications for preterm birth and prematurity. Sci Rep. 2017;7:40194.
This MonthMarch 2018
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j c i . o r g / t h i s - m o n t h m a r c h 2 0 1 82
research
Editor’s picks
on the jci cover
Coagulation factor FXII’s double duty in neutrophil-mediated wound inflammationThe coagulation cascade comprises a series of enzyme-activating reactions between circulating coagulation factors and cofactors that culminate in blood clot formation. However, the potential functions of inactive, or zymogen, coagulation factors are often unappreciated. The zymogen form of coagulation factor XII (FXII) is known to interact with fibroblasts as well as endothelial, immune, and muscle cells via urokinase plasminogen activator receptor (uPAR), suggesting that FXII may possess enzyme-independent activity. In this issue, Stavrou et al. pursue zymogen FXII’s functions following observations of reduced uPAR-mediated wound angiogenesis in FXII-deficient mice. FXII loss impaired neutrophil recruitment to wound sites, leading to lower inflammation and enhanced wound healing. The researchers reveal that neutrophil-derived FXII signals through uPAR to promote increases in adhesion, migration, chemotaxis, and neutrophil extracellular trap (NET) formation. A proteolyti-cally inactive FXII mutant recapitulated this downstream signaling, confirming that the response is zymogen mediated. These findings identify the FXII/uPAR axis as a driver of neutrophil-mediated inflammation, highlighting a potential target for inflammatory disease. The cover image depicts translocation of FXII (green) to the plasma membrane of activated neutrophils, where it acts as an autocrine signal to enhance neutrophil functions, including the release of NETs (purple lines). Image credit: Erika Woodrum.
Factor XII and uPAR upregulate neutrophil functions to influence wound healingEvi X. Stavrou, Chao Fang, Kara L. Bane, Andy T. Long, Clément Naudin, Erdem Kucukal, Agharnan Gandhi, Adina Brett-Morris, Michele M. Mumaw, Sudeh Izadmehr, Alona Merkulova, Cindy C. Reynolds, Omar Alhalabi, Lalitha Nayak, Wen-Mei Yu, Cheng-Kui Qu, Howard J. Meyerson, George R. Dubyak, Umut A. Gurkan, Marvin T. Nieman, Anirban Sen Gupta, Thomas Renné, and Alvin H. Schmaier http://jci.me/92880
inflammation
cardiology
Common SNP influences cardiac sodium channel expression and heart failureThe voltage-gated channel encoded by SCN5A gates the sodium current that initiates cardiac action potentials. Mutations in SCN5A cause arrhythmias and cardiomyopathies, but the mechanisms regulating this gene’s expression are largely unknown. Work led by Ryan Boudreau and Barry London has identified that the microRNA miR-24 suppresses SCN5A expression and that this regulatory interaction is modulated by a common SNP in the coding sequence. The SNP was linked to reductions in SCN5A expression in cardiac tissue from heart donors and to adverse outcomes in 2 distinct cohorts of heart failure patients, but surprisingly was not linked to increased arrhythmias. In rat-derived cardiomyocytes, miR-24 potently suppressed sodium currents to a magnitude similar to Scn5a-targeting siRNA, further supporting the notion that miR-24 influences SCN5A expression. In the accompanying Commentary, David Park and Glenn Fishman weigh the evidence that modest decreases in SCN5A expression may increase risk of heart failure.
A common variant alters SCN5A–miR-24 interaction and associates with heart failure mortalityXiaoming Zhang, Jin-Young Yoon, Michael Morley, Jared M. McLendon, Kranti A. Mapuskar, Rebecca Gutmann, Haider Mehdi, Heather L. Bloom, Samuel C. Dudley, Patrick T. Ellinor, Alaa A. Shalaby, Raul Weiss, W.H. Wilson Tang, Christine S. Moravec, Madhurmeet Singh, Anne L. Taylor, Clyde W. Yancy, Arthur M. Feldman, Dennis M. McNamara, Kaikobad Irani, Douglas R. Spitz, Patrick Breheny, Kenneth B. Margulies, Barry London, and Ryan L. Boudreau http://jci.me/95710
Related CommentarySCN5A: the greatest HITS collectionDavid S. Park and Glenn I. Fishman http://jci.me/99927
j c i . o r g / t h i s - m o n t h m a r c h 2 0 1 8 3
JCI | Research: Editor’s picks
clinical medicine
Mucus plugs exacerbate airway obstruction in some patients with severe asthmaMucus plugs contribute to mechanisms of airflow obstruction in cases of fatal asthma, but whether mucus plugs play a role in airflow obstruction in chronic severe asthma is unknown. Eleanor Dunican and colleagues, in collaboration with the NIH Severe Asthma Research Program, evaluated 146 subjects with asthma and 22 controls using multidetector computed tomography scans of the lungs. Mucus plugs were found in 58% of asthmatic subjects compared with 4.5% in healthy controls, and the presence of mucus plugs was strongly associated with measures of airflow obstruction and airway eosinophilia. Experiments performed in mucus gel models indicate that the products of eosinophil peroxidase promote mucus plug formation. In the accompanying Commentary, Steve Georas highlights the utility of noninvasive imaging in evaluating mechanisms of airflow obstruction in chronic severe asthma.
Mucus plugs in patients with asthma linked to eosinophilia and airflow obstructionEleanor M. Dunican, Brett M. Elicker, David S. Gierada, Scott K. Nagle, Mark L. Schiebler, John D. Newell, Wilfred W. Raymond, Marrah E. Lachowicz-Scroggins, Selena Di Maio, Eric A. Hoffman, Mario Castro, Sean B. Fain, Nizar N. Jarjour, Elliot Israel, Bruce D. Levy, Serpil C. Erzurum, Sally E. Wenzel, Deborah A. Meyers, Eugene R. Bleecker, Brenda R. Phillips, David T. Mauger, Erin D. Gordon, Prescott G. Woodruff, Michael C. Peters, John V. Fahy, and the National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP) http://jci.me/95693
Related CommentaryAll plugged up — noninvasive mucus score to assess airway dysfunction in asthmaSteve N. Georas http://jci.me/99726
Hypothalamic Snord116 deletion reproduces late-stage hyperphagia in Prader-Willi syndrome modelPrader-Willi syndrome (PWS) manifests as early developmental growth delay and later-onset hyperphagia and severe obesity. PWS is linked to deletions on human chromosome 15, with a minimal deletion region on the paternal chromosome encompassing SNORD116, a noncoding RNA. Ablating paternal Snord116 in mice (Snord116+/–P) recapitulates early growth impairments observed in PWS-affected individuals, but does not replicate the hyperphagia or obesity that characterizes PWS in older individuals. Noting that hypothalamic SNORD116 expression increases at weaning age in mice, Joseph Polex-Wolf and colleagues examined the effects of hypothalamus-specific deletion of Snord116 in adult mice. In contrast to Snord116+/–P mice, hypothalamic SNORD116-deficient mice developed marked hyperphagia, and five of twenty-one animals developed obesity. Although human SNORD116 loss has been linked to dysfunction of the appetite-controlling leptin/melanocortin pathway, corresponding deficits were not observed in hypothalamic SNORD116-deficient mice. The accompanying Commentary by Juan Rodriguez and Jeffrey Zigman examines questions that remain unresolved in the wake of this finding.
Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndromeJoseph Polex-Wolf, Brian Y.H. Lam, Rachel Larder, John Tadross, Debra Rimmington, Fàtima Bosch, Verónica Jiménez Cenzano, Eduard Ayuso, Marcella K.L. Ma, Kara Rainbow, Anthony P. Coll, Stephen O’Rahilly, and Giles S.H. Yeo http://jci.me/97007
Related CommentaryHypothalamic loss of Snord116 and Prader-Willi syndrome hyperphagia: the buck stops here?Juan A. Rodriguez and Jeffrey M. Zigman http://jci.me/99725
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JCI | Research: Editor’s picks
vascular biology
Hemoglobin-activated macrophages promote atherosclerotic plaque angiogenesis and progressionAtherosclerotic plaques recruit proinflammatory M1 macrophages that stimulate foam cell formation and promote plaque progression. Plaques also recruit alternatively activated macrophages, which are thought to offset the atherogenic effects of M1 by promoting the repair and resolution of inflammation. A study from Aloke Finn’s laboratory investigates the contribution of a subset of alternatively activated macrophages to atherogenesis. M(Hb) macrophages are distinguished by expression of CD163, a receptor for hemoglobin:haptoglobin complexes and can be found at sites of plaque rupture. The research-ers’ examination of human carotid plaques revealed that M(Hb) macrophage abundance correlated with advanced plaque progression, intraplaque angiogenesis, and vascular permeability. Although M(Hb) macrophages did not stimulate foam cell formation, they were associated with increased plaque progression and inflammation in a mouse model. These findings suggest a proatherogenic rather than protective role for this macrophage subtype. Benoit Pourcet and Bart Staels highlight this distinct pathogenic mechanism underlying plaque progression in an accompanying Commentary.
CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosisLiang Guo, Hirokuni Akahori, Emanuel Harari, Samantha L. Smith, Rohini Polavarapu, Vinit Karmali, Fumiyuki Otsuka, Rachel L. Gannon, Ryan E. Braumann, Megan H. Dickinson, Anuj Gupta, Audrey L. Jenkins, Michael J. Lipinski, Johoon Kim, Peter Chhour, Paul S. de Vries, Hiroyuki Jinnouchi, Robert Kutys, Hiroyoshi Mori, Matthew D. Kutyna, Sho Torii, Atsushi Sakamoto, Cheol Ung Choi, Qi Cheng, Megan L. Grove, Mariem A. Sawan, Yin Zhang, Yihai Cao, Frank D. Kolodgie, David P. Cormode, Dan E. Arking, Eric Boerwinkle, Alanna C. Morrison, Jeanette Erdmann, Nona Sotoodehnia, Renu Virmani, and Aloke V. Finn http://jci.me/93025
Related CommentaryAlternative macrophages in atherosclerosis: not always protective!Benoit Pourcet and Bart Staels http://jci.me/120123
LRP1 balances lipid metabolism and glucose homeostasis in diet-induced obesityβ Cell hyperplasia compensates for the peripheral insulin resistance that characterizes type II diabetes. This compensation ensures that β cells can produce sufficient insulin to maintain systemic glucose homeostasis. Risheng Ye and colleagues investigated how the regulation of lipid metabolism contributes to compensatory β cell proliferation, focusing on the role of the LDL receptor LRP1. They observed that mice with Lrp1-deficient β cells were unable to maintain glucose tolerance during high-fat feeding as a result of reduced β cell volume and impaired insulin secretion (see the accompanying image). Interestingly, Lrp1 deficiency also enhanced lipid metabolism in β cells, an effect mediated by the transcriptional regulator PPARγ2. Moreover, overexpression of PPARγ2 impaired insulin signaling, suggesting that lipid metabolism improves at the expense of glucose handling. Together, these findings indicate that LRP1 plays an important but complex role in balancing lipid metabolism and glucose homeostasis in response to nutrient flux.
Intracellular lipid metabolism impairs β cell compensation during diet-induced obesityRisheng Ye, Ruth Gordillo, Mengle Shao, Toshiharu Onodera, Zhe Chen, Shiuhwei Chen, Xiaoli Lin, Jeffrey A. SoRelle, Xiaohong Li, Miao Tang, Mark P. Keller, Regina Kuliawat, Alan D. Attie, Rana K. Gupta, William L. Holland, Bruce Beutler, Joachim Herz, and Philipp E. Scherer http://jci.me/97702
j c i . o r g / t h i s - m o n t h m a r c h 2 0 1 8 5
JCI | Research: Editor’s picks
pulmonology
Claudin-18 and YAP interact to control proliferation in lung epithelium
Lung microanatomy promotes staphylococcal infection and antibiotic resistance
Claudin proteins play essential roles in forming and maintaining the tight junctions that regulate paracel-lular permeability and cell polarity. Although claudin dysregulation has been observed in cancer, the interactions linking claudins to cancer progression are not well described. Beiyun Zhou, Per Flodby, and colleagues found that claudin-18 regulates lung, stomach, and kidney size in mice, suggesting a role for this protein in controlling cell proliferation. Their studies reveal that loss of claudin-18 drives expansion of a progenitor cell population in lung epithelium. Mechanistically, they determined that claudin-18 ablation increased activation of YAP, a known regulator of stem cell and tumor proliferation. They further report increased lung tumor incidence in claudin-18–deficient mice (see the associated image) and reductions in claudin-18 expression in human lung adenocarcinomas. In an accompanying Commentary, Darrell Kotton indicates that the involvement of claudin-18 in both homeostatic and malignant processes raises the possibility that it could be targeted therapeutically.
Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesisBeiyun Zhou, Per Flodby, Jiao Luo, Dan R. Castillo, Yixin Liu, Fa-Xing Yu, Alicia McConnell, Bino Varghese, Guanglei Li, Nyam-Osor Chimge, Mitsuhiro Sunohara, Michael N. Koss, Wafaa Elatre, Peter Conti, Janice M. Liebler, Chenchen Yang, Crystal N. Marconett, Ite A. Laird-Offringa, Parviz Minoo, Kunliang Guan, Barry R. Stripp, Edward D. Crandall, and Zea Borok http://jci.me/90429
Related CommentaryClaudin-18: unexpected regulator of lung alveolar epithelial cell proliferationDarrell N. Kotton http://jci.me/99799
The Staphylococcus aureus strain USA300 causes severe infections and death, despite timely therapy with antibiotics that are effective in vitro. Little is known about how USA300 initiates infection and resists antibiotics in vivo. Jaime Hook and colleagues imaged live lung alveoli in the first minutes of USA300 lung infection. The inhaled bacteria rapidly formed stable, solute-impermeable microaggregates in structural niches, where they secreted α-hemolysin toxin and induced localized epithelial injury (see the accompanying image). The injury induced an epithelial cytosolic Ca2+ increase, which spread to uninfected alveoli through intercellular gap junctions, causing pulmonary edema. Antibiotic pretreatment increased survival in mice infected with mutant USA300 lacking the aggregation-promoting factor PhnD, but it had no effect on mice infected with WT USA300. These findings reveal a critical role for alveolar microanatomy in the initiation of lung infection and microbial resistance to antibiotic therapy.
Disruption of staphylococcal aggregation protects against lethal lung injuryJaime L. Hook, Mohammad N. Islam, Dane Parker, Alice S. Prince, Sunita Bhattacharya, and Jahar Bhattacharya http://jci.me/95823
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JCI | Research: Editor’s picks
viewpoint
Interpreting the cardiovascular safety of antihyperglycemic therapies
gastroenterology
A BATF-dependent Th1 subset drives acute intestinal inflammationGraft-versus-host disease (GVHD) is a systemic inflammatory complication of allogeneic hematopoietic cell transplantation (allo-HCT) that can lead to life-threaten-ing intestinal tissue damage. Evelyn Ullrich, Benjamin Abendroth, and coworkers discovered an indispensable role for the transcription factor BATF in initiating acute intestinal GVHD in a mouse model of allo-HCT (see the associated image). Their study identifies a subset of gut-infiltrating, IL-7 receptor+ GM–CSF+ T cells that was sufficient to induce intestinal GVHD in the mouse model. Gene expression studies suggest that a similar BATF-expressing subset may be present in patients with GVHD. Although BATF is normally linked to Th17 cell development, this BATF-dependent cell population displayed a phenotype that more closely resembled Th1 cells. In the accompanying Commentary, Defu Zeng describes a potential therapeutic axis that could enable cell-specific targeting for acute intestinal inflammation in GVHD.
BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host diseaseEvelyn Ullrich, Benjamin Abendroth, Johanna Rothamer, Carina Huber, Maike Büttner-Herold, Vera Buchele, Tina Vogler, Thomas Longerich, Sebastian Zundler, Simon Völkl, Andreas Beilhack, Stefan Rose-John, Stefan Wirtz, Georg F. Weber, Sakhila Ghimire, Marina Kreutz, Ernst Holler, Andreas Mackensen, Markus F. Neurath, and Kai Hildner http://jci.me/89242
Related CommentaryNewly found arsons ignite the fire of gut GVHDDefu Zeng http://jci.me/98685
The uncontrolled hyperglycemia that characterizes diabetes puts patients at risk of microvascular diseases (including retinopathy, nephropathy, and peripheral neuropathy) as well as macrovascular diseases (such as stroke and coronary artery disease). While antihyper-glycemic therapies mitigate the incidence of microvascular conditions, some groups have
questioned their safety as it relates to macrovascular conditions. In 2008, recom-mendations by an FDA advisory committee advocated for implementation of careful trial design to evaluate and limit cardiovascular risk in study participants. In this month’s Viewpoint, Simeon Taylor and Bruce Leslie summarize a decade’s worth of cardiovascular
outcome trials of diabetes treatments and infer lessons that may improve the design of future studies.
Cardiovascular outcome trials of diabetes drugs: lessons learnedSimeon I. Taylor and Bruce R. Leslie http://jci.me/99820
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Current research articles
AIDS/HIVHIV latency is reversed by ACSS2-driven histone crotonylationGuochun Jiang, Don Nguyen, Nancie M. Archin, Steven A. Yukl, Gema Méndez-Lagares, Yuyang Tang, Maher M. Elsheikh, George R. Thompson III, Dennis J. Hartigan-O’Connor, David M. Margolis, Joseph K. Wong, and Satya Dandekar http://jci.me/98071
bone biologyVhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolismNaomi Dirckx, Robert J. Tower, Evi M. Mercken, Roman Vangoitsenhoven, Caroline Moreau-Triby, Tom Breugelmans, Elena Nefyodova, Ruben Cardoen, Chantal Mathieu, Bart Van der Schueren, Cyrille B. Confavreux, Thomas L. Clemens, and Christa Maes http://jci.me/97794
cardiologyPhysiological genomics identifies genetic modifiers of long QT syndrome type 2 severitySam Chai, Xiaoping Wan, Angelina Ramirez-Navarro, Paul J. Tesar, Elizabeth S. Kaufman, Eckhard Ficker, Alfred L. George Jr., and Isabelle Deschênes http://jci.me/94996
A common variant alters SCN5A–miR-24 interaction and associates with heart failure mortality p. 2Xiaoming Zhang, Jin-Young Yoon, Michael Morley, Jared M. McLendon, Kranti A. Mapuskar, Rebecca Gutmann, Haider Mehdi, Heather L. Bloom, Samuel C. Dudley, Patrick T. Ellinor, Alaa A. Shalaby, Raul Weiss, W.H. Wilson Tang, Christine S. Moravec, Madhurmeet Singh, Anne L. Taylor, Clyde W. Yancy, Arthur M. Feldman, Dennis M. McNamara, Kaikobad Irani, Douglas R. Spitz, Patrick Breheny, Kenneth B. Margulies, Barry London, and Ryan L. Boudreau http://jci.me/95710
clinical medicineRandomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactionsChuang-Wei Wang, Lan-Yan Yang, Chun-Bing Chen, Hsin-Chun Ho, Shuen-Iu Hung, Chih-Hsun Yang, Chee-Jen Chang, Shih-Chi Su, Rosaline Chung-Yee Hui, See-Wen Chin, Li-Fang Huang, Yang Yu-Wei Lin, Wei-Yang Chang, Wen-Lang Fan, Chin-Yi Yang, Ji-Chen Ho, Ya-Ching Chang, Chun-Wei Lu, Wen-Hung Chung, and the Taiwan Severe Cutaneous Adverse Reaction (TSCAR) Consortium http://jci.me/93349
Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction p. 3Eleanor M. Dunican, Brett M. Elicker, David S. Gierada, Scott K. Nagle, Mark L. Schiebler, John D. Newell, Wilfred W. Raymond, Marrah E. Lachowicz-Scroggins, Selena Di Maio, Eric A. Hoffman, Mario Castro, Sean B. Fain, Nizar N. Jarjour, Elliot Israel, Bruce D. Levy, Serpil C. Erzurum, Sally E. Wenzel, Deborah A. Meyers, Eugene R. Bleecker, Brenda R. Phillips, David T. Mauger, Erin D. Gordon, Prescott G. Woodruff, Michael C. Peters, John V. Fahy, and the National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP) http://jci.me/95693
gastroenterologyBATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease p. 6Evelyn Ullrich, Benjamin Abendroth, Johanna Rothamer, Carina Huber, Maike Büttner-Herold, Vera Buchele, Tina Vogler, Thomas Longerich, Sebastian Zundler, Simon Völkl, Andreas Beilhack, Stefan Rose-John, Stefan Wirtz, Georg F. Weber, Sakhila Ghimire, Marina Kreutz, Ernst Holler, Andreas Mackensen, Markus F. Neurath, and Kai Hildner http://jci.me/89242
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Current research articles
geneticsTIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutationsYouJin Lee, Per Harald Jonson, Jaakko Sarparanta, Johanna Palmio, Mohona Sarkar, Anna Vihola, Anni Evilä, Tiina Suominen, Sini Penttilä, Marco Savarese, Mridul Johari, Marie-Christine Minot, David Hilton-Jones, Paul Maddison, Patrick Chinnery, Jens Reimann, Cornelia Kornblum, Torsten Kraya, Stephan Zierz, Carolyn Sue, Hans Goebel, Asim Azfer, Stuart H. Ralston, Peter Hackman,
Robert C. Bucelli, J. Paul Taylor, Conrad C. Weihl, and Bjarne Udd http://jci.me/97103
Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome p. 3Joseph Polex-Wolf, Brian Y.H. Lam, Rachel Larder, John Tadross, Debra Rimmington, Fàtima Bosch, Verónica Jiménez Cenzano, Eduard Ayuso, Marcella K.L. Ma, Kara Rainbow, Anthony P. Coll, Stephen O’Rahilly, and Giles S.H. Yeo http://jci.me/97007
immunologySTAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cellsYuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, and Bo Huang http://jci.me/96329
Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfectionCarly A. Dillen, Bret L. Pinsker, Alina I. Marusina, Alexander A. Merleev, Orly N. Farber, Haiyun Liu, Nathan K. Archer, Da B. Lee, Yu Wang, Roger V. Ortines, Steven K. Lee, Mark C. Marchitto, Shuting S. Cai, Alyssa G. Ashbaugh, Larissa S. May, Steven M. Holland, Alexandra F. Freeman, Loren G. Miller, Michael R. Yeaman, Scott I. Simon, Joshua D. Milner, Emanual Maverakis, and Lloyd S. Miller http://jci.me/96481
Microglia are required for protection against lethal coronavirus encephalitis in miceD. Lori Wheeler, Alan Sariol, David K. Meyerholz, and Stanley Perlman http://jci.me/97229
inflammationFactor XII and uPAR upregulate neutrophil functions to influence wound healing p. 2Evi X. Stavrou, Chao Fang, Kara L. Bane, Andy T. Long, Clément Naudin, Erdem Kucukal, Agharnan Gandhi, Adina Brett-Morris, Michele M. Mumaw, Sudeh Izadmehr, Alona Merkulova, Cindy C. Reynolds, Omar Alhalabi, Lalitha Naya, Wen-Mei Yu, Cheng-Kui Qu, Howard J. Meyerson, George R. Dubyak, Umut A. Gurkan, Marvin T. Nieman, Anirban Sen Gupta, Thomas Renné, and Alvin H. Schmaier http://jci.me/92880
metabolismIntracellular lipid metabolism impairs β cell compensation during diet-induced obesity p. 4Risheng Ye, Ruth Gordillo, Mengle Shao, Toshiharu Onodera, Zhe Chen, Shiuhwei Chen, Xiaoli Lin, Jeffrey A. SoRelle, Xiaohong Li, Miao Tang, Mark P. Keller, Regina Kuliawat, Alan D. Attie, Rana K. Gupta, William L. Holland, Bruce Beutler, Joachim Herz, and Philipp E. Scherer http://jci.me/97702
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Flip issue to read JCI Insight content.
neuroscienceHypothalamic ER–associated degradation regulates POMC maturation, feeding, and age-associated obesityGeun Hyang Kim, Guojun Shi, Diane R.M. Somlo, Leena Haataja, Soobin Song, Qiaoming Long, Eduardo A. Nillni, Malcolm J. Low, Peter Arvan, Martin G. Myers Jr., and Ling Qi http://jci.me/96420
Severe peri-ictal respiratory dysfunction is common in Dravet syndromeYuJaung Kim, Eduardo Bravo, Caitlin K. Thirnbeck, Lori A. Smith-Mellecker, Se Hee Kim, Brian K. Gehlbach, Linda C. Laux, Xiuqiong Zhou, Douglas R. Nordli Jr., and George B. Richerson http://jci.me/94999
oncologyHippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancerSun-Hye Jeong, Han-Byul Kim, Min-Chul Kim, Ji-min Lee, Jae Ho Lee, Jeong-Hwan Kim, Jin-Woo Kim, Woong-Yang Park, Seon-Young Kim, Jae Bum Kim, Haeryoung Kim, Jin-Man Kim, Hueng-Sik Choi, and Dae-Sik Lim http://jci.me/95802
pulmonologyClaudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis p. 5Beiyun Zhou, Per Flodby, Jiao Luo, Dan R. Castillo, Yixin Liu, Fa-Xing Yu, Alicia McConnell, Bino Varghese, Guanglei Li, Nyam-Osor Chimge, Mitsuhiro Sunohara, Michael N. Koss, Wafaa Elatre, Peter Conti, Janice M. Liebler, Chenchen Yang, Crystal N. Marconett, Ite A. Laird-Offringa, Parviz Minoo, Kunliang Guan, Barry R. Stripp, Edward D. Crandall, and Zea Borok http://jci.me/90429
Disruption of staphylococcal aggregation protects against lethal lung injury p. 5Jaime L. Hook, Mohammad N. Islam, Dane Parker, Alice S. Prince, Sunita Bhattacharya, and Jahar Bhattacharya http://jci.me/95823
vascular biologyCD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis p. 4Liang Guo, Hirokuni Akahori, Emanuel Harari, Samantha L. Smith, Rohini Polavarapu, Vinit Karmali, Fumiyuki Otsuka, Rachel L. Gannon, Ryan E. Braumann, Megan H. Dickinson, Anuj Gupta, Audrey L. Jenkins, Michael J. Lipinski, Johoon Kim, Peter Chhour, Paul S. de Vries, Hiroyuki Jinnouchi, Robert Kutys, Hiroyoshi Mori, Matthew D. Kutyna, Sho Torii, Atsushi Sakamoto, Cheol Ung Choi,
Qi Cheng, Megan L. Grove, Mariem A. Sawan, Yin Zhang, Yihai Cao, Frank D. Kolodgie, David P. Cormode, Dan E. Arking, Eric Boerwinkle, Alanna C. Morrison, Jeanette Erdmann, Nona Sotoodehnia, Renu Virmani, and Aloke V. Finn http://jci.me/93025
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For JCI InsightEditorHoward A. RockmanAssociate EditorsRodger A. Liddle, Yiping YangExecutive EditorSarah C. JacksonScience EditorCorinne Williams
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For JCI Insight online: jci.me/insight/3/3jci.me/insight/3/4
mTOR linked to chronic obstructive pulmonary disease phenotypes
On the JCI Insight cover
Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and progres-sive loss of lung function due to alveolar tissue destruction. There is no cure for this devastating disease, and the factors that drive lung destruction are not clear, though enhanced cell senescence has been proposed as an underlying factor in disease pathology. In this month’s
JCI Insight, Amal Houssaini and colleagues evaluated the contribution of mTOR to COPD-associated lung cell senescence. Compared with those from age-matched smokers without COPD, lung tissue and cell cultures derived from patients with COPD had a higher level of senescent cells that corresponded to an increase in mTOR signaling. Moreover, treatment of COPD-derived cultures with a low dose of the mTOR inhibitor rapamycin ameliorated senescence and reduced the proinflammatory senescence–associated secretory phenotype. In murine models, overexpression of mTOR specifically in the lung vasculature or alveolar epithelium recapitulated COPD-associated alterations, including lung cell senescence, along with the development of emphysema, pulmonary hypertension, and inflammation. Together, the results of this study implicate enhanced mTOR signaling in COPD pathogenesis and support further evalua-tion of mTOR as a therapeutic target for COPD. The cover image shows macro-phage (CD68, red) infiltration into the alveolar spaces as a result of transgenic overexpression of mTOR, specifically in lung endothelial cells. Smooth muscle actin is shown in green, and nuclei are stained with DAPI.
mTOR pathway activation drives lung cell senescence and emphysemaAmal Houssaini, Marielle Breau, Kanny Kebe, Shariq Abid, Elisabeth Marcos, Larissa Lipskaia, Dominique Rideau, Aurelien Parpaleix, Jin Huang, Valerie Amsellem, Nora Vienney, Pierre Validire, Bernard Maitre, Aya Attwe, Christina Lukas, David Vindrieux, Jorge Boczkowski, Genevieve Derumeaux, Mario Pende, David Bernard, Silke Meiners, and Serge Adnot http://jci.me/93203
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Editor’s picks
immunology
IL-15 dosing affects NK cell immunotherapy efficacy
Genetically modified DC vaccine for acute leukemiaDC-based tumor vaccines have been explored as a potential strategy for acute leukemia. Unfortunately, despite their demonstrated ability to activate tumor antigen–targeting T cells, DC vaccines have had limited efficacy that has been linked to maintenance of self-tolerance in recipients. Danhong Wang, Xue Huang, and colleagues developed a genetically modified DC (gmDC) that combines tumor antigens survivin and MUC1; bacterial flagellin, which promotes DC maturation; and an RNA interference module to target the immune checkpoint protein SOCS1. In a small cohort of patients with relapsed acute leukemia after allogenic hematopoietic stem cell transplantation, those that received gmDC had improved survival rates compared with those that received an infusion of donor lymphocytes. More-over, 10 of 12 acute myeloid leukemia patients with early molecular relapse had complete remission following gmDC vaccination. None of the patients in the study exhibited high-grade graft-versus-host disease, thereby supporting gmDC as a promising therapy for acute leukemia.
Efficacy of intracellular immune checkpoint-silenced DC vaccineDanhong Wang, Xue F. Huang, Bangxing Hong, Xiao-Tong Song, Liangding Hu, Min Jiang, Bin Zhang, Hongmei Ning, Yuhang Li, Chen Xu, Xiao Lou, Botao Li, Zhiyong Yu, Jiangwei Hu, Jianlin Chen, Fan Yang, Haiyan Gao, Guoliang Ding, Lianming Liao, Lisa Rollins, Lindsey Jones, Si-Yi Chen, and Hu Chen http://jci.me/98368
Due to their ability to directly lyse target cells, NK cell–based strategies have become an attractive option for cancer immunotherapy. As with other immune cell–based strategies, maintaining NK cell function and persistence following transfer is critical for efficacy. As IL-15 promotes NK cell development
and function, this cytokine is being explored clinically to boost the efficacy of NK cell therapy. Martin Felices and colleagues evaluated the effects of different IL-15 exposure strategies on human NK cell function and expansion. Compared with cells intermittently exposed to IL-15, NK cells continuously exposed to
IL-15 had diminished function and reduced capacity for tumor control (see the accompanying image) that coincided with reduced fatty acid oxidation. Inhibition of mTOR, which is downstream of IL-15, restored NK cell functionality, supporting mTOR activation as a mediator of exhaustion in these cells. The results of this study support careful IL-15 dosing for maximal NK cell function.
Continuous treatment with IL-15 exhausts human NK cells via a metabolic defectMartin Felices, Alexander J. Lenvik, Ron McElmurry, Sami Chu, Peter Hinderlie, Laura Bendzick, Melissa A. Geller, Jakub Tolar, Bruce R. Blazar, and Jeffrey S. Miller http://jci.me/96219
metabolism
HDL subspecies determines metabolic benefitCardiovascular disease (CVD) is the leading cause of death in the United States, and studies have shown that high HDL levels strongly associate with a lower risk of CVD. However, approaches to increase HDL cholesterol (HDL-C) alone do not reduce CVD risk, indicating that perhaps other HDL cargo are important for its beneficial effects. Allyson Morton, Manja Koch, and colleagues determined how apolipoproteins E and CIII (apoE and CIII) regulate HDL metabolism and coronary heart disease (CHD) risk utilizing individual and population-based studies as complementary approaches. In a small cohort of patients, HDL-apoE was shown to promote reverse cholesterol transport, while the presence of apoCIII on HDL-apoE counteracted this. Supporting the clinical importance of the kinetics studies, analysis of 1,949 CHD cases and 1,750 controls showed that higher HDL-apoE is linked to lower CHD risk, but only in the absence of HDL-apoCIII. Together, these results demonstrate the importance of HDL subspecies as defined by their specific protein cargo in determining CHD risk.
Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease riskAllyson M. Morton, Manja Koch, Carlos O. Mendivil, Jeremy D. Furtado, Anne Tjønneland, Kim Overvad, Liyun Wang, Majken K. Jensen, and Frank M. Sacks http://jci.me/98045
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JCI Insight | Editor’s picks
endocrinology
Subcellular location of lipids in skeletal muscle influences insulin sensitivitySkeletal muscle is important for postprandial glucose clearance and is critical for mainte-nance of glucose homeostasis. Type 2 diabetes–associated insulin resistance in this tissue is thought to result from the accumula-tion of diacylglycerols (DAGs) and sphingolip-ids; however, it is not clear whether the location of these lipids contributes to the loss of insulin sensitivity. Leigh Perreault and colleagues evaluated the subcellular localiza-tion of DAGs and sphingolipids in muscle biopsies collected from endurance athletes, lean individuals, and obese men and women with and without type 2 diabetes. Insulin sensitivity inversely related to ceramides and sphingomyelins in the sarcolemma and to ceramides in the mitochondrial/ER and nuclear fractions. Mitochondrial/ER- and nuclear-localized 1,2-DAGs positively related to insulin sensitively. Cytosolic lipids 1,3-DAG, dihydrocer-amides, and glucosylceramides had no relation to differences in insulin sensitivity between groups. Together, the results of this study demonstrate that the complex compartmental differences, and not total differences, in lipids should be considered for developing strategies for treating insulin resistance.
Intracellular localization of diacylglycerols and sphingolipids influences insulin sensitivity and mitochondrial function in human skeletal muscleLeigh Perreault, Sean A. Newsom, Allison Strauss, Anna Kerege, Darcy E. Kahn, Kathleen A. Harrison, Janet K. Snell-Bergeon, Travis Nemkov, Angelo D’Alessandro, Matthew R. Jackman, Paul S. MacLean, and Bryan C. Bergman http://jci.me/96805
genetics
Markers of anti–PD-1/PD-L1 response in head and neck cancerFor some patients with platinum-resistant squamous cell carcinoma of the head and neck (SCCHN), inhibition of programmed cell death protein-1 (PD-1) and/or its ligand PD-L1 is an effective strategy. It is not clear why some patients benefit from PD-1/PD-L1 inhibition, and there are no reliable markers to identify those who will respond. Glenn Hanna and colleagues evaluated a cohort of SCCHN patients prior to and after PD-1/L1 therapy. Prior chemotherapy was associated with improved survival compared with surgery and/or radiation therapy alone. Virus-positive patients exhibited an increase in overall survival and a lower mutational burden. In virus-negative individuals, frameshift mutations in tumor suppressor genes, increased mutational burden, and the presence of tumor CD8+ T cell infiltrates predicted PD-1/L1 treatment benefit. Expression of TIM-3/LAG-3 with PD-1 on T cells was higher in nonresponders, suggesting adaptive immune resistance. The results of this study identify additional markers for predicting and evaluating individual responses to PD-1/L1 inhibition.
Frameshift events predict anti–PD-1/L1 response in head and neck cancerGlenn J. Hanna, Patrick Lizotte, Megan Cavanaugh, Frank C. Kuo, Priyanka Shivdasani, Alexander Frieden, Nicole G. Chau, Jonathan D. Schoenfeld, Jochen H. Lorch, Ravindra Uppaluri, Laura E. MacConaill, and Robert I. Haddad http://jci.me/98811
perspective
Collaboration and a good model: discussing the discovery of TORA seminal paper published by Joe Heitman, Rao Movva, and Mike Hall in 1991 identified FKB12 and TOR proteins as the downstream targets of rapamycin and related compounds. This work set the stage for subsequent studies that have shown that the TOR proteins are central regulators of cell growth and metabolism in response to nutritional cues. Alterations in TOR signaling are linked to a variety of diseases, and TOR remains an attractive therapeutic target. In this issue of JCI Insight, Joe Heitman and Rao Movva discuss how this collaboration came about, the use of yeast as a model system, and the importance of partnerships between academic institutes and industry. The accompanying image shows (left to right) Drs. Hall, Heitman, and Movva.
Talking TOR: a conversation with Joe Heitman and Rao MovvaCorinne L. Williams http://jci.me/99816
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JCI Insight | Editor’s picks
muscle biology
TGF-β–activated kinase 1 keeps skeletal muscle in balance
development
Lack of T cell population shift predicts preterm infant outcomesPremature infants are at high risk of respiratory complications following viral infection compared with their full-term counterparts. The factors that underlie discrepant outcomes following infection are not fully understood; however, incomplete immune cell maturation has been proposed as a possible driver. Kristin Scheible and colleagues evaluated T cells from 157 infants born between 23 and 42 weeks of gestation and identified gestational age–dependent differences in T cell populations. Moreover, these postnatal differences in T cell development were predictive of respiratory outcomes at 1 year of age. Specifi-cally, naive CD4+ T cells were shown to shift from a CD31–TNF-α+ phenotype to a predominantly CD31+IL-8+ phenotype at mid- to late gestation, and preterm infants with a CD31–TNF-α+CD4+ T cell bias were at much higher risk of respiratory complications. This work lays the foundation for future studies to elucidate how this population arises and may be enhanced in preterm infants.
T cell developmental arrest in former premature infants increases risk of respiratory morbidity later in infancyKristin M. Scheible, Jason Emo, Nathan Laniewski, Andrea M. Baran, Derick R. Peterson, Jeanne Holden-Wiltse, Sanjukta Bandyopadhyay, Andrew G. Straw, Heidie Huyck, John M. Ashton, Kelly Schooping Tripi, Karan Arul, Elizabeth Werner, Tanya Scalise, Deanna Maffett, Mary Caserta, Rita M. Ryan, Anne Marie Reynolds, Clement L. Ren, David J. Topham, Thomas J. Mariani, and Gloria S. Pryhuber http://jci.me/96724
Multiple signaling pathways converge to regulate skeletal muscle mass, and aberrant activation or inhibition of signaling dynamics can lead to muscle wasting and loss of function. Sajedah Hindi and colleagues investigated the contribution of TGF-β–activated kinase 1 (TAK1), which is responsible for context-dependent regulation of multiple pathways, to skeletal muscle homeostasis. Inducible depletion of TAK1 specifically in skeletal muscle resulted in severe muscle wasting in adult mice that associated with protein synthesis inhibition, proteolysis, and alteration in AMPK and mTOR signaling. Loss of TAK1 in skeletal muscle resulted in accumulation of dysfunctional mitochondria (see the accompanying image) and increased oxidative stress. TAK1 deficiency also exacerbated muscle wasting in response to denervation. Last, in a model of overload-induced hypertrophy, TAK1 activity was markedly increased, and TAK1 inactivation prevented hypertrophy in this model. Together, these results support TAK1 as an important mediator of skeletal muscle mass.
TAK1 regulates skeletal muscle mass and mitochondrial functionSajedah M. Hindi, Shuichi Sato, Guangyan Xiong, Kyle R. Bohnert, Andrew A. Gibb, Yann S. Gallot, Joseph D. McMillan, Bradford G. Hill, Shizuka Uchida, and Ashok Kumar http://jci.me/98441
microbiology
Gut microbiota influences response to adoptive cell therapyAlterations in gut microbiota have been linked to a variety of diseases and have been shown to influence T cell responses and function. Mireia Uribe-Herranz and colleagues systematically evaluated the effect of gut microbiome composition on antitumor responses following adoptive cell therapy (ACT) in a murine cervical cancer model. Mice from different vendors had discrepant responses to ACT and distinct differences in gut microbiota. Treatment of mice that were less responsive to ACT with vancomycin improved tumor remission but had no effect on those animals in which ACT was already effective. Moreover, fecal transplant between animals from different vendors determined the efficacy of ACT. Beneficial responses were associated with increased CD8α+ DCs and increased IL-12. This study highlights the influence that gut microbiome composition has on ACT efficacy and suggests that strategies to favorably alter the microbiota may improve overall responses to ACT.
Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12Mireia Uribe-Herranz, Kyle Bittinger, Stavros Rafail, Sonia Guedan, Stefano Pierini, Ceylan Tanes, Alex Ganetsky, Mark A. Morgan, Saar Gill, Janos L. Tanyi, Frederic D. Bushman, Carl H. June, and Andrea Facciabene http://jci.me/94952
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Current articles
Osteoblastic heparan sulfate regulates osteoprotegerin function and bone massSatoshi Nozawa, Toshihiro Inubushi, Fumitoshi Irie, Iori Takigami, Kazu Matsumoto, Katsuji Shimizu, Haruhiko Akiyama, and Yu Yamaguchi http://jci.me/89624
mTOR pathway activation drives lung cell senescence and emphysema p. 10Amal Houssaini, Marielle Breau, Kanny Kebe, Shariq Abid, Elisabeth Marcos, Larissa Lipskaia, Dominique Rideau, Aurelien Parpaleix, Jin Huang, Valerie Amsellem, Nora Vienney, Pierre Validire, Bernard Maitre, Aya Attwe, Christina Lukas, David Vindrieux, Jorge Boczkowski, Genevieve Derumeaux, Mario Pende, David Bernard, Silke Meiners, and Serge Adnot http://jci.me/93203
Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunctionMichael Fricker, Bridie J. Goggins, Sean Mateer, Bernadette Jones, Richard Y. Kim, Shaan L. Gellatly, Andrew G. Jarnicki, Nicholas Powell, Brian G. Oliver, Graham Radford-Smith, Nicholas J. Talley, Marjorie M. Walker, Simon Keely, and Philip M. Hansbro http://jci.me/94040
RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyaseMitsuru Imamura, Jong-Seok Moon, Kuei-Pin Chung, Kiichi Nakahira, Thangamani Muthukumar, Roman Shingarev, Stefan W. Ryter, Augustine M.K. Choi, and Mary E. Choi http://jci.me/94979
Swiprosin-1 deficiency impairs macrophage immune response of septic miceSu Zhang, Ye Tu, Yi-Ming Sun, Ya Li, Rong-Mei Wang, Yongbing Cao, Ling Li, Li-Chao Zhang, and Zhi-Bin Wang http://jci.me/95396
The homozygous CX3CR1-M280 mutation impairs human monocyte survivalAmanda L. Collar, Muthulekha Swamydas, Morgan O’Hayre, Md Sanaullah Sajib, Kevin W. Hoffman, Satya P. Singh, Ahmad Mourad, Melissa D. Johnson, Elise M.N. Ferre, Joshua M. Farber, Jean K. Lim, Constantinos M. Mikelis, J. Silvio Gutkind, and Michail S. Lionakis http://jci.me/95417
Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect p. 11Martin Felices, Alexander J. Lenvik, Ron McElmurry, Sami Chu, Peter Hinderlie, Laura Bendzick, Melissa A. Geller, Jakub Tolar, Bruce R. Blazar, and Jeffrey S. Miller http://jci.me/96219
Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritisCaressa Lietman, Brian Wu, Sarah Lechner, Andrew Shinar, Madhur Sehgal, Evgeny Rossomacha, Poulami Datta, Anirudh Sharma, Rajiv Gandhi, Mohit Kapoor, and Pampee P. Young http://jci.me/96308
Intracellular localization of diacylglycerols and sphingolipids influences insulin sensitivity and mitochondrial function in human skeletal muscle p. 12Leigh Perreault, Sean A. Newsom, Allison Strauss, Anna Kerege, Darcy E. Kahn, Kathleen A. Harrison, Janet K. Snell-Bergeon, Travis Nemkov, Angelo D’Alessandro, Matthew R. Jackman, Paul S. MacLean, and Bryan C. Bergman http://jci.me/96805
Thrombospondin-1 protects against pathogen-induced lung injury by limiting extracellular matrix proteolysisYanyan Qu, Tolani Olonisakin, William Bain, Jill Zupetic, Rebecca Brown, Mei Hulver, Zeyu Xiong, Jesus Tejero, Robert M.Q. Shanks, Jennifer M. Bomberger, Vaughn S. Cooper, Michael E. Zegans, Hyunryul Ryu, Jongyoon Han, Joseph Pilewski, Anuradha Ray, Zhenyu Cheng, Prabir Ray, and Janet S. Lee http://jci.me/96914
Virus-like infection induces human β cell dedifferentiationMasaya Oshima, Klaus-Peter Knoch, Marc Diedisheim, Antje Petzold, Pierre Cattan, Marco Bugliani, Piero Marchetti, Pratik Choudhary, Guo-Cai Huang, Stefan R. Bornstein, Michele Solimena, Olivier Albagli-Curiel, and Raphael Scharfmann http://jci.me/97732
Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cellsYanling Wang, Haineng Xu, Tianrun Liu, Menggui Huang, Param-Puneet Butter, Chunsheng Li, Lin Zhang, Gary D. Kao, Yanqing Gong, Amit Maity, Constantinos Koumenis, and Yi Fan http://jci.me/98096
Restoration of the type I IFN–IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD miceM. Jubayer Rahman, Kameron B. Rodrigues, Juan A. Quiel, Yi Liu, Vipul Bhargava, Yongge Zhao, Chie Hotta-Iwamura, Han-Yu Shih, Annie W. Lau-Kilby, Allison M.W. Malloy, Timothy W. Thoner, and Kristin V. Tarbell http://jci.me/97843
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Current articles
Goblet cell loss abrogates ocular surface immune toleranceByung Yi Ko, Yangyan Xiao, Flavia L. Barbosa, Cintia S. de Paiva, and Stephen C. Pflugfelder http://jci.me/98222
Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injuryEmma Lefrançais, Beñat Mallavia, Hanjing Zhuo, Carolyn S. Calfee, and Mark R. Looney http://jci.me/98178
TAK1 regulates skeletal muscle mass and mitochondrial function p. 13Sajedah M. Hindi, Shuichi Sato, Guangyan Xiong, Kyle R. Bohner, Andrew A. Gibb, Yann S. Gallot, Joseph D. McMillan, Bradford G. Hill, Shizuka Uchida, and Ashok Kumar http://jci.me/98441
iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarctionDamien N. Barnette, Thomas J. Cahill, Mala Gunadasa-Rohling, Carolyn A. Carr, Matthew Freeman, and Paul R. Riley http://jci.me/98268
Efficacy of intracellular immune checkpoint-silenced DC vaccine p. 11Danhong Wang, Xue F. Huang, Bangxing Hong, Xiao-Tong Song, Liangding Hu, Min Jiang, Bin Zhang, Hongmei Ning, Yuhang Li, Chen Xu, Xiao Lou, Botao Li, Zhiyong Yu, Jiangwei Hu, Jianlin Chen, Fan Yang, Haiyan Gao, Guoliang Ding, Lianming Liao, Lisa Rollins, Lindsey Jones, Si-Yi Chen, and Hu Chen http://jci.me/98368
Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epitheliaValeria Tomati, Emanuela Caci, Loretta Ferrera, Emanuela Pesce, Elvira Sondo, Deborah M. Cholon, Nancy L. Quinney, Susan E. Boyles, Andrea Armirotti, Roberto Ravazzolo, Luis J.V. Galietta, Martina Gentzsch, and Nicoletta Pedemonte http://jci.me/98699
TNF receptor–activated factor 2 mediates cardiac protection through noncanonical NF-κB signalingSarah Evans, Huei-Ping Tzeng, Deborah J. Veis, Scot Matkovich, Carla Weinheimer, Attila Kovacs, Philip M. Barger, and Douglas L. Mann http://jci.me/98278
Von Hippel–Lindau mutations disrupt vascular patterning and maturation via NotchAlexandra Arreola, Laura Beth Payne, Morgan H. Julian, Aguirre A. de Cubas, Anthony B. Daniels, Sarah Taylor, Huaning Zhao, Jordan Darden, Victoria L. Bautch, W. Kimryn Rathmell, and John C. Chappell http://jci.me/92193
Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumorsStergios J. Moschos, Ryan J. Sullivan, Wen-Jen Hwu, Ramesh K. Ramanathan, Alex A. Adjei, Peter C. Fong, Ronnie Shapira-Frommer, Hussein A. Tawbi, Joseph Rubino, Thomas Rush, Da Zhang, Nathan R. Miselis, Ahmed A. Samatar, Patrick Chun, Eric H. Rubin, James Schiller, Brian J. Long, Priya Dayananth, Donna Carr, Paul Kirschmeier, W. Robert Bishop, Yongqi Deng, Alan Cooper, Gerald W. Shipps, Blanca Homet Moreno, Lidia Robert, Antoni Ribas, and Keith T. Flaherty http://jci.me/92352
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Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalitiesMarta Christov, Abbe R. Clark, Braden Corbin, Samy Hakroush, Eugene P. Rhee, Hiroaki Saito, Dan Brooks, Eric Hesse, Mary Bouxsein, Niels Galjart, Ji Yong Jung, Peter Mundel, Harald Jüppner, Astrid Weins, and Anna Greka http://jci.me/95091
Angiokine Wisp-1 is increased in myocardial infarction and regulates cardiac endothelial signalingLillianne H. Wright, Daniel J. Herr, Symone S. Brown, Harinath Kasiganesan, and Donald R. Menick http://jci.me/95824
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Nitric oxide–sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fractionNicola Wilck, Lajos Markó, András Balogh, Kristin Kräker, Florian Herse, Hendrik Bartolomaeus, István A. Szijártó, Maik Gollasch, Nadine Reichhart, Olaf Strauß, Arnd Heuser, Damian Brockschnieder, Axel Kretschmer, Ralf Lesche, Florian Sohler, Johannes-Peter Stasch, Peter Sandner, Friedrich C. Luft, Dominik N. Müller, Ralf Dechend, and Nadine Haase http://jci.me/96006
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Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cellsHidetoshi Tsuda, Charles A. Su, Toshiaki Tanaka, Katayoun Ayasoufi, Booki Min, Anna Valujskikh, and Robert L. Fairchild http://jci.me/96940
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TCR-mimic bispecific antibodies targeting LMP2A show potent activity against EBV malignanciesMahiuddin Ahmed, Andres Lopez-Albaitero, Dmitry Pankov, Brian H. Santich, Hong Liu, Su Yan, Jingyi Xiang, Pei Wang, Aisha N. Hasan, Annamalai Selvakumar, Richard J. O’Reilly, Cheng Liu, and Nai-Kong V. Cheung http://jci.me/97805
PTEN deficiency promotes pathological vascular remodeling of human coronary arteriesKaren S. Moulton, Marcella Li, Keith Strand, Shawna Burgett, Penn McClatchey, Rebecca Tucker, Seth B. Furgeson, Sizhao Lu, Bruce Kirkpatrick, Joseph C. Cleveland, Raphael A. Nemenoff, Amrut V. Ambardekar, and Mary C.M. Weiser-Evans http://jci.me/97228
A specific phosphorylation regulates the protective role of αA-crystallin in diabetesAnne Ruebsam, Jennifer E. Dulle, Angela M. Myers, Dhananjay Sakrikar, Katelyn M. Green, Naheed W. Khan, Kevin Schey, and Patrice E. Fort http://jci.me/97919
Lipid abnormalities in atopic skin are driven by type 2 cytokinesEvgeny Berdyshev, Elena Goleva, Irina Bronova, Nathan Dyjack, Cydney Rios, John Jung, Patricia Taylor, Mingeum Jeong, Clifton F. Hall, Brittany N. Richers, Kathryn A. Norquest, Tao Zheng, Max A. Seibold, and Donald Y.M. Leung http://jci.me/98006
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