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ALSO IN THIS ISSUE:

Calcineurin is an age-dependent effector of β cell proliferation 2

Asymmetric proteasome activity drives T cell fate 3

Tumor-secreted GDF-15 suppresses macrophage immune surveillance 3

p53 dysregulation implicated in premature aging disorder 6

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October 2017

Angiopoietin/Tie2 signaling maintains Schlemm’s canal function p. 1

This Month

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This MonthOctober 2017

Angiopoietin/Tie2 signaling maintains Schlemm’s canal function and ocular fluid homeostasis

On the JCI cover

In glaucoma, increased intraocular pressure damages retinal ganglion cells, causing irreversible vision loss. The pathological increase of intraocular pressure is induced by fluid accumulation within the eye as a consequence of impaired aqueous humor out-flow. Schlemm’s canal (SC) is a specialized vascular structure encircling the cornea that functions as the major conduit for fluid outflow from the eye’s ante-rior chamber. Recent studies have demonstrated the requirement for angiopoietin/Tie2 signaling during

SC development, but this pathway may also support SC integrity to maintain fluid homeostasis during adulthood. In this issue of the JCI, Jaeryung Kim, Dae-Young Park, and colleagues show a critical role for the angiopoietin/Tie2 axis in maintaining SC integrity. Inducible deletion of endothelial Tie2 in adult mice led to elevation in ocular pressure and gradual visual impairment. The researchers also observed severe SC regression and glaucoma-like phenotypes when the Tie2 ligands angiopoietin 1 and 2 were ablated in adult mice, indicat-ing that Tie2/angiopoietin signaling is required for SC maintenance in addition to maturation. Tie2 activation reversed SC impairment in angiopoietin-deficient mice and in aged mice, which exhibited reductions in Tie2 and angiopoietin expression compared with younger mice. In the accompanying Commentary, Jeremiah Bernier-Latmani and Tatiana Petrova discuss future therapeutic prospects raised by the involvement of angiopoietin/Tie2 signaling impairment in the pathogenesis of adult-onset primary open-angle glaucoma. The cover image visualizes Schlemm’s canal in green and red with associated aqueous veins (thin red vessels) and episcleral veins (thick red vessels). Image credit: Jaeryung Kim.

Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucomaJaeryung Kim, Dae-Young Park, Hosung Bae, Do Young Park, Dongkyu Kim, Choong-kun Lee, Sukhyun Song, Tae-Young Chung, Dong Hui Lim, Yoshiaki Kubota, Young-Kwon Hong, Yulong He, Hellmut G. Augustin, Guillermo Oliver, and Gou Young Koh http://jci.me/94668

Related CommentaryAll TIEd up: mechanisms of Schlemm’s canal maintenanceJeremiah Bernier-Latmani and Tatiana V. Petrova http://jci.me/96840

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.

Jeanne M. Clark

j c i . o r g / t h i s - m o n t h o c t o b e r 2 0 1 72

research

Editor’s picks

endocrinology

GLP-1 receptors differentially engage calcineurin in adult and juvenile β cells

ER-associated degradation deficiency impairs prohormone processing to cause polyuria

Related CommentaryMice deficient for ERAD machinery component Sel1L develop central diabetes insipidusDaniel G. Bichet and Yoann Lussier http://jci.me/96839

The peptide hormone arginine vasopressin (AVP) regulates water balance by activating renal water conservation mechanisms in response to increasing plasma osmolarity. Peptide hormone synthesis begins in the ER, where hormone precursors, or prohormones, undergo protein folding and cleavage to become biologically active, mature peptides. ER-associated degradation (ERAD) involving the Sel1L-Hrd1 protein complex sequesters and destroys misfolded peptide hormones during the maturation process. In characterizing mice with inducible or AVP neuron–specific Sel1L deletion, Ling Qi’s laboratory found that these animals develop central diabetes insipidus, a condition caused by AVP deficiency. Further investigation revealed that disruptions in

ERAD lead to retention of proAVP aggregates in the ER (see the associated image). These aggregates continuously recruit newly synthesized proAVP via aberrant disulfide bonds, preventing maturation into active AVP. In the accompanying Commentary, Daniel Bichet and Yoann Lussier highlight the critical role of ERAD in maintaining a suitable environment for prohormone processing in the ER.

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasisGuojun Shi, Diane Somlo, Geun Hyang Kim, Cristina Prescianotto-Baschong, Shengyi Sun, Nicole Beuret, Qiaoming Long, Jonas Rutishauser, Peter Arvan, Martin Spiess, and Ling Qi http://jci.me/94771

β Cell expansion occurs in the postnatal period, but proliferation rates decline in adolescence. Discovering ways to stimulate proliferation in adult human β cells has been challenging and compounded by differences in rodent and human islets. Stimulating glucagon-like peptide receptor (GLP-1R) signaling promotes insulin secretion, with GLP-1R activation being useful in the treatment of type 2 diabetes. Chunhua Dai, Yan Hang, and colleagues quantified β cell proliferation in juvenile (<10 years of age) and adult human islet grafts and evaluated age-dependent responses to GLP-1R stimulation. GLP-1R activation evoked insulin secretion in transplanted juvenile and adult human islets but promoted β cell proliferation only in juvenile islets (see the accompanying image). Although GLP-1R activated

calcineurin-independent pathways in adult islets, only juvenile β cells had the ability to signal through calcineurin/NFAT, which enabled their proliferative responses. This pathway regulating age-dependent β cell proliferation could potentially be exploited to expand deficient β cell populations in patients with diabetes.

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signalingChunhua Dai, Yan Hang, Alena Shostak, Greg Poffenberger, Nathaniel Hart, Nripesh Prasad, Neil Phillips, Shawn E. Levy, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Seung K. Kim, and Alvin C. Powers http://jci.me/91761

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JCI | Research: Editor’s picks

immunology

oncology

NF-κB promotes GDF-15 secretion to inactivate macrophage antitumor immune surveillanceTumors develop mechanisms to escape immune surveillance, an immune cell–mediated process that eliminates neoplastic cells. A key feature of immune surveillance is macrophage infiltration into a developing tumor. Tumor-initiating cells produce the transcription factor NF-κB to protect themselves from cytotoxic attack, but the mechanisms supporting this strategy of immune evasion are unknown. Nivedita Ratnam and labmates discovered that NF-κB directly regulates the expression of growth and differentiation factor 15 (GDF-15) in tumor cells (see the accompanying image). Depleting GDF-15 in xenograft and orthotopic cancer models delayed tumor development and increased levels of tumor-targeting macrophages, supporting its role as a tumor-protecting factor. Finally, the researchers determined that tumor-derived GDF-15 acts on macrophages to reduce secretion of proapoptotic TNF, nitric oxide, and ROS, permitting successful proliferation of cancer cells.

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor developmentNivedita M. Ratnam, Jennifer M. Peterson, Erin E. Talbert, Katherine J. Ladner, Priyani V. Rajasekera, Carl R. Schmidt, Mary E. Dillhoff, Benjamin J. Swanson, Ericka Haverick, Raleigh D. Kladney, Terence M. Williams, Gustavo W. Leone, David J. Wang, and Denis C. Guttridge http://jci.me/91561

Asymmetric proteasome activity regulates effector and memory T cell fatesMicrobial infections, cancer, and autoimmunity trigger activation, proliferation, and differentiation of naive CD8+ T cells into daughter cells with distinct effector and memory fates. Drawing from observations that asymmetric CD8+ T cell division results in unequal proteasome segregation between daughter cells, Christella Widjaja and colleagues hypothesized that differences in proteasome activity regulate these fate decisions. First-division daughters of activated CD8+ T cells that acquired a pre-effector phenotype exhibited lower levels of proteasome activity than daughters that acquired a pre-memory phenotype. Moreover, pharmacological reduction of proteasome activity during differentiation enhanced effector-like characteristics, whereas increasing proteasome activity promoted attributes of memory cells. Manipulations of proteasome activity were associated with Myc-dependent changes in cellular metabolism. These findings suggest that increasing proteasome activity during CD8+ T cell differentiation may be a strategy to promote memory T cell generation and enhance immunologic memory.

Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specificationChristella E. Widjaja, Jocelyn G. Olvera, Patrick J. Metz, Anthony T. Phan, Jeffrey N. Savas, Gerjan de Bruin, Yves Leestemaker, Celia R. Berkers, Annemieke de Jong, Bogdan I. Florea, Kathleen Fisch, Justine Lopez, Stephanie H. Kim, Daniel A. Garcia, Stephen Searles, Jack D. Bui, Aaron N. Chang, John R. Yates III, Ananda W. Goldrath, Hermen S. Overkleeft, Huib Ovaa, and John T. Chang http://jci.me/90895

Syntaphilin responds to microenvironment conditions to optimize proliferation-motility decisionsTumor survival depends on the ability to adapt to unfavorable conditions, including hypoxia, nutrient depletion, and immunological attack. Fluctuations in nutrient and oxygen availability necessitate a mechanism that balances nutrient-intensive cellular proliferation and metastatic motility. Cecilia Caino, Jae Ho Seo, and colleagues report that an alternatively spliced isoform of the cytoskeleton regulator syntaphilin coordinates mitochondrial distribution within tumor cells in response to stress stimuli. High levels of this isoform promoted tumor cell proliferation at the expense of motility. In contrast, microenvironmen-tal stressors such as hypoxia decreased syntaphilin levels, enabling mitochondrial trafficking to the cortical cytoskeleton to support tumor cell motility. These observations indicate that syntaphilin is part of a pathway that gauges conditions in the tumor microenvironment to optimize decisions between proliferation and metastasis.

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancerM. Cecilia Caino, Jae Ho Seo, Yuan Wang, Dayana B. Rivadeneira, Dmitry I. Gabrilovich, Eui Tae Kim, Ashani T. Weeraratna, Lucia R. Languino, and Dario C. Altieri http://jci.me/93172

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JCI | Research: Editor’s picks

hematology

autoimmunity

miR-146a blocks Th17 differentiation from autoreactive CD4+ T cellsActivated CD4+ T cells differentiate into Th, Treg, and follicular B helper T cell subsets with distinct antipathogen, cellular, and humoral responses. Proinflammatory Th17 cells are implicated in the pathogenesis of autoimmune diseases, which may arise from the dysfunctional regulation of differentiation pathways. Bo Li, Xi Wang, and colleagues identify miR-146a as an important control point in the development of pathogenic Th17 cells. In a mouse model of multiple sclerosis, miR-146a–deficient mice exhibited severe Th17-mediated responses to autoantigen as well as enhanced CNS inflammation (see the accompanying image). miR-146a deficiency skewed autoreactive CD4+ T cell cytokine expression toward conditions that favored Th17 polarization. The NF-κB signaling transducer molecules TRAF6 and IRAK1 were identified as miR-146a targets that mediate Th17-polarizing conditions. This work offers insights into potential therapeutic approaches targeting molecular regulators of pathogenic Th17 differentiation in autoimmune conditions.

miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunityBo Li, Xi Wang, In Young Choi, Yu-Chen Wang, Siyuan Liu, Alexander T. Pham, Heesung Moon, Drake J. Smith, Dinesh S. Rao, Mark P. Boldin, and Lili Yang http://jci.me/94012

Haploinsufficiency for DNA methyltransferase DNMT3A lays groundwork for myeloid malignanciesIn acute myeloid leukemia (AML), cooperating mutations can sometimes act to prevent stem/progenitor cell differentiation and also drive the proliferation of immature subclones. Dominant negative mutations that suppress function of the DNA methyltransferase DNMT3A are common initiating events for AML patients with normal karyotypes. However, heterozygous truncation and premature stop mutations in DNMT3A also are found in some AML patients, and their role in leukemogenesis is less clear. Christopher Cole, David Russler-Germain, Shamika Ketkar, and colleagues show that three DNMT3A truncation mutations are null alleles. They therefore characterized the effects of DNMT3A haploinsufficiency using Dnmt3a+/– mice. Although young Dnmt3a+/– mice exhibited normal hematopoiesis, they developed myeloid skewing over time that increased the likelihood of acquiring cooperating mutations and subsequent myeloid malignancies. While the mechanisms responsible remain unclear, these data suggest that DNMT3A haplosufficiency is indeed a predisposing factor for the initiation of AML.

Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignanciesChristopher B. Cole, David A. Russler-Germain, Shamika Ketkar, Angela M. Verdoni, Amanda M. Smith, Celia V. Bangert, Nichole M. Helton, Mindy Guo, Jeffery M. Klco, Shelly O’Laughlin, Catrina Fronick, Robert Fulton, Gue Su Chang, Allegra A. Petti, Christopher A. Miller, and Timothy J. Ley http://jci.me/93041

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JCI | Research: Editor’s picks

metabolism

Skeletal muscle Gα13 regulates myofiber phenotype and whole-body metabolismThe energetic demands of skeletal muscle contribute substantially to whole-body metabolic capacity. Muscle contains a mixture of intercon-vertible oxidative and nonoxidative myofibers, and increases in the highly metabolic oxidative phenotype are associated with a lower risk for adiposity and insulin resistance. Ja Hyun Koo and coworkers examined the role of the G protein Gα13 in regulating myofiber phenotype, reprogramming, and whole-body metabolism. In mice, skeletal muscle–specific loss of Gα13 led to increases in oxidative myofibers and muscle glucose metabolism (see the accompanying image), exercise performance, and insulin sensitivity. Gα13-deficient mice were also resistant to weight gain and adiposity during high-fat feeding as a result of enhanced energy expenditure. The researchers determined that Gα13 suppresses oxidative reprogramming by regulating Rho kinase 2, leading to inactivation of the transcription factor NFATc1. Together, these findings provide a basis for examining Gα13-regulated pathways as therapeutic targets in metabolic diseases.

ER phospholipid remodeling alters lipogenesis in response to nutrient availabilitySterol regulatory element–binding proteins SREBP1 and SREBP2 coordinate gene expression required for lipogenesis and cholesterol biosynthesis, respec-tively. Whereas cholesterol and sterol levels influence SREBP2 maturation and activation, the mechanisms that regulate SREBP1 are less clear. Xin Rong and coworkers investigated the involvement of liver X receptor (LXR) in SREBP1-mediated lipogenesis. They found that activating LXR induces transcription of the phospholipid-remodeling enzyme LPCAT3, leading to increases in levels of the mature SREBP1c isoform. They further demonstrated that LPCAT3 modifies the phospholipid composition of the ER membrane to facilitate the movement of immature SREBP1 to Golgi, promoting SREBP1 maturation. LPCAT3-dependent modifications to ER phospholipid composition also controlled lipogenic gene transcription during feeding and in obese mice. These findings delineate a mechanism governing the maturation and activity of SREBP1 that may have important therapeutic implications in the treatment of metabolic disorders.

ER phospholipid composition modulates lipogenesis during feeding and in obesityXin Rong, Bo Wang, Elisa N.D. Palladino, Thomas Q. de Aguiar Vallim, David A. Ford, and Peter Tontonoz http://jci.me/93616

RNA-binding protein ZFP36L1 maintains bile acid homeostasis and lipid absorptionImbalances in bile acid levels result in metabolic disturbances that may underlie the pathogenic accumulation of lipids. The nuclear receptor FXR maintains bile acid homeostasis by calibrating the expression of proteins involved in the synthesis of bile acid, including its rate-limiting enzyme CYP7A1. Elizabeth Tarling and colleagues have now revealed a role for the RNA-binding protein ZFP36L1 in FXR-mediated degradation of CYP7A1. Activated FXR induces the transcription of ZFP36L1, which targets and destroys CYP7A1-encoding mRNA. In gain- and loss-of-function studies, the researchers observed that ZFP36L1 regulates the expression of Cyp7a1 along with bile acid levels. Hepatic ZFP36L1 deficiency protected mice from diet-induced adiposity and reduced levels of liver triglycerides and cholesterol. Overall, these findings warrant further investigation of ZFP36L1-mediated regulation of lipid absorption in the pathogenesis of metabolic disorders.

RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolismElizabeth J. Tarling, Bethan L. Clifford, Joan Cheng, Pauline Morand, Angela Cheng, Ellen Lester, Tamer Sallam, Martin Turner, and Thomas Q. de Aguiar Vallim http://jci.me/94029

Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolismJa Hyun Koo, Tae Hyun Kim, Shi-Young Park, Min Sung Joo, Chang Yeob Han, Cheol Soo Choi, and Sang Geon Kim http://jci.me/92067

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aging

viewpoint

Aberrant expression of p53 linked to premature aging disorder

Reflecting on the reality of human genome editing

The tumor suppressor p53 responds to cellular stress by regulating physiological pathways involved in cell-cycle progression, apoptosis, senescence, and more. Strong evidence links inactivating mutations in p53 to cancer risk, but the relationship between p53 and aging remains unclear. Davor Lessel, Danyi Wu, and colleagues hypothesized that abnormal aging processes arise from disruptions in an autoregulatory loop between p53 and the E3 ubiquitin ligase MDM2. The researchers identified an MDM2 loss-of-function mutation in a patient with segmental progeroid

syndrome, a disorder characterized by premature aging. Under normal conditions, the p53/MDM2 axis maintains p53 expression at very low cellular levels. However, in this patient, loss of MDM2 activity drove increases in p53 expression and stability. In an Mdm2-deficient zebrafish model, ectopic expression of a corresponding Mdm2 mutation was unable to rescue a severe apoptotic phenotype. Altogether, these findings suggest that aberrant p53 regulation may underlie premature aging disorders.

Dysfunction of the MDM2/p53 axis is linked to premature agingDavor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K. Alwasiyah, Bidisha Saha, Fuki M. Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R. Tong, Chen Katz, George M. Martin, Junko Oshima, Carol Prives, and Christian Kubisch http://jci.me/92171

Genome editing tools represent powerful advances to biomedical research as well as an opportunity to develop potentially curative treatments for human genetic diseases. A recent study in Nature reports the first CRISPR-mediated human embryo editing to be performed in the United States. Hong Ma et al. targeted a cardiomy-opathy-associated MYBPC3 mutation in the paternal allele. They found that CRISPR-Cas9 injection could correct the deleterious allele using the wild-type maternal allele as a template. Though preliminary, the work raises questions about the future of genome editing technology in medicine. Srinivasan Chandrasegaran, C. Korin Bullen, and Dana Carroll review the details of the study and consider the unresolved mechanistic, therapeutic, and ethical issues associated with human genome editing in this issue’s Viewpoint article.

Genome editing of human embryos: to edit or not to edit, that is the questionSrinivasan Chandrasegaran, C. Korin Bullen, and Dana Carroll http://jci.me/96962

JCI | Research: Editor’s picks

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Current research articles

aids/hivNo evidence of HIV replication in children on antiretroviral therapyGert U. Van Zyl, Mary Grace Katusiime, Ann Wiegand, William R. McManus, Michael J. Bale, Elias K. Halvas, Brian Luke, Valerie F. Boltz, Jonathan Spindler, Barbara Laughton, Susan Engelbrecht, John M. Coffin, Mark F. Cotton, Wei Shao, John W. Mellors, and Mary F. Kearney http://jci.me/94582

agingDysfunction of the MDM2/p53 axis is linked to premature aging p. 6Davor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K. Alwasiyah, Bidisha Saha, Fuki M. Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R. Tong, Chen Katz, George M. Martin, Junko Oshimo, Carol Prives, and Christian Kubisch http://jci.me/92171

autoimmunitymiR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity p. 4Bo Li, Xi Wang, In Young Choi, Yu-Chen Wang, Siyuan Liu, Alexander T. Pham, Heesung Moon, Drake J. Smith, Dinesh S. Rao, Mark P. Boldin, and Lili Yang http://jci.me/94012

bone biologyIncreased intracellular proteolysis reduces disease severity in an ER stress–associated dwarfismLorna A. Mullan, Ewa J. Mularczyk, Louise H. Kung, Mitra Forouhan, Jordan M.A. Wragg, Royston Goodacre, John F. Bateman, Eileithyia Swanton, Michael D. Briggs, and Raymond P. Boot-Handford http://jci.me/93094

mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagyRosa Bartolomeo, Laura Cinque, Chiara De Leonibus, Alison Forrester, Anna Chiara Salzano, Jlenia Monfregola, Emanuela De Gennaro, Edoardo Nusco, Isabella Azario, Carmela Lanzara, Marta Serafini, Beth Levine, Andrea Ballabio, and Carmine Settembre http://jci.me/94130

cardiologyFibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosisHadi Khalil, Onur Kanisicak, Vikram Prasad, Robert N. Correll, Xing Fu, Tobias Schips, Ronald J. Vagnozzi, Ruijie Liu, Thanh Huynh, Se-Jin Lee, Jason Karch, and Jeffery D. Molkentin http://jci.me/94753

endocrinologyAge-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling p. 2Chunhua Dai, Yan Hang, Alena Shostak, Greg Poffenberger, Nathaniel Hart, Nripesh Prasad, Neil Phillips, Shawn E. Levy, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Seung K. Kim, and Alvin C. Powers http://jci.me/91761

p53 expression in fibroblasts

Collagen trafficking in chrondrocytes

Transplanted human b cells

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Current research articles

endocrinologyER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis p. 2Guojun Shi, Diane Somlo, Geun Hyang Kim, Cristina Prescianotto-Baschong, Shengyi Sun, Nicole Beuret, Qiaoming Long, Jonas Rutishauser, Peter Arvan, Martin Spiess, and Ling Qi http://jci.me/94771

hematologyHaploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies p. 4Christopher B. Cole, David A. Russler-Germain, Shamika Ketkar, Angela M. Verdoni, Amanda M. Smith, Celia V. Bangert, Nichole M. Helton, Mindy Guo, Jeffery M. Klco, Shelly O’Laughlin, Catrina Fronick, Robert Fulton, Gue Su Chang, Allegra A. Petti, Christopher A. Miller, and Timothy J. Ley http://jci.me/93041

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell nicheIoannis Mitroulis, Lan-Sun Chen, Rahim Pal Singh, Ioannis Kourtzelis, Matina Economopoulou, Tetsuhiro Kajikawa, Maria Troullinaki, Athanasios Ziogas, Klara Ruppova, Kavita Hosur, Tomoki Maekawa, Baomei Wang, Pallavi Subramanian, Torsten Tonn, Panayotis Verginis, Malte von Bonin, Manja Wobus, Martin Bornhäuser, Tatyana Grinenko, Marianna Di Scala, Andres Hidalgo, Ben Wielockx, George Hajishengallis, and Triantafyllos Chavakis http://jci.me/92571

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemiaStefan P. Tarnawsky, Rebecca J. Chan, and Mervin C. Yoder http://jci.me/94031

immunologyProteasome activity regulates CD8+ T lymphocyte metabolism and fate specification p. 3Christella E. Widjaja, Jocelyn G. Olvera, Patrick J. Metz, Anthony T. Phan, Jeffrey N. Savas, Gerjan de Bruin, Yves Leestemaker, Celia R. Berkers, Annemieke de Jong, Bogdan I. Florea, Kathleen Fisch, Justine Lopez, Stephanie H. Kim, Daniel A. Garcia, Stephen Searles, Jack D. Bui, Aaron N. Chang, John R. Yates III, Ananda W. Goldrath, Hermen S. Overkleeft, Huib Ovaa, and John T. Chang http://jci.me/90895

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development p.3Nivedita M. Ratnam, Jennifer M. Peterson, Erin E. Talbert, Katherine J. Ladner, Priyani V. Rajasekera, Carl R. Schmidt, Mary E. Dillhoff, Benjamin J. Swanson, Ericka Haverick, Raleigh D. Kladney, Terence M. Williams, Gustavo W. Leone, David J. Wang, and Denis C. Guttridge http://jci.me/91561

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinasesHiroshi Nishi, Kazuhiro Furuhashi, Xavier Cullere, Gurpanna Saggu, Mark J. Miller, Yunfeng Chen, Florencia Rosetti, Samantha L. Hamilton, Lihua Yang, Spencer P. Pittman, Jiexi Liao, Jan M. Herter, Jeffrey C. Berry, Daniel J. DeAngelo, Cheng Zhu, George C. Tsokos, and Tanya N. Mayadas http://jci.me/94039

metabolismGα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism p. 5Ja Hyun Koo, Tae Hyun Kim, Shi-Young Park, Min Sung Joo, Chang Yeob Han, Cheol Soo Choi, and Sang Geon Kim http://jci.me/92067Tibialis anterior muscle fibers

Leukemic myeloid cells

Pancreatic tumor cells

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ER phospholipid composition modulates lipogenesis during feeding and in obesity p. 5Xin Rong, Bo Wang, Elisa N.D. Palladino, Thomas Q. de Aguiar Vallim, David A. Ford, and Peter Tontonoz http://jci.me/93616

RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism p. 5Elizabeth J. Tarling, Bethan L. Clifford, Joan Cheng, Pauline Morand, Angela Cheng, Ellen Lester, Tamer Sallam, Martin Turner, and Thomas Q. de Aguiar Vallim http://jci.me/94029

muscle biologyDeficiency in Kelch protein Klhl31 causes congenital myopathy in miceJames B. Papizan, Glynnis A. Garry, Svetlana Brezprozvannaya, John R. McAnally, Rhonda Bassel-Duby, Ning Liu, and Eric N. Olson http://jci.me/93445

0ncologySyntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer p. 3M. Cecilia Caino, Jae Ho Seo, Yuan Wang, Dayana B. Rivadeneira, Dmitry I. Gabrilovich, Eui Tae Kim, Ashani T. Weeraratna, Lucia R. Languino, and Dario C. Altieri http://jci.me/93172

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agentsMinfeng Chen, Xueping Lei, Changzheng Shi, Maohua Huang, Xiaobo Li, Baojian Wu, Zhengqiu Li, Weili Han, Bin Du, Jianyang Hu, Qiulin Nie, Weiqian Mai, Nan Ma, Nanhui Xu, Xinyi Zhang, Chunlin Fan, Aihua Hong, Minghan Xia, Liangping Luo, Ande Ma, Hongsheng Li, Qiang Yu, Heru Chen, Dongmei Zhang, and Wencai Ye http://jci.me/94258

ophthalmologyImpaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma p. 1Jaeryung Kim, Dae-Young Park, Hosung Bae, Do Young Park, Dongkyu Kim, Choong-kun Lee, Sukhyun Song, Tae-Young Chung, Dong Hui Lim, Yoshiaki Kubota, Young-Kwon Hong, Yulong He, Hellmut G. Augustin, Guillermo Oliver, and Gou Young Koh http://jci.me/94668

pulmonologyFibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosisYing Wei, Thomas J. Kim, David H. Peng, Dana Duan, Don L. Gibbons, Mitsuo Yamauchi, Julia R. Jackson, Claude J. Le Saux, Cheresa Calhoun, Jay Peters, Rik Derynck, Bradley J. Backes, and Harold A. Chapman http://jci.me/94624

Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cellsGregory A. Wasserman, Aleksander D. Szymaniak, Anne C. Hinds, Kazuko Yamamoto, Hirofumi Kamata, Nicole M.S. Smith, Kristie L. Hilliard, Claudia Carrieri, Adam T. Labadorf, Lee J. Quinton, Xingbin Ai, Xaralabos Varelas, Felicia Chen, Joseph P. Mizgerd, Alan Fine, Dónal O’Carroll, and Matthew R. Jones http://jci.me/94639

virologyHerpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitisNaoto Koyanagi, Takahiko Imai, Keiko Shindo, Ayuko Sato, Wataru Fujii, Takeshi Ichinohe, Naoki Takemura, Shigeru Kakuta, Satoshi Uematsu, Hiroshi Kiyono, Yuhei Maruzuru, Jun Arii, Akihisa Kato, and Yasushi Kawaguchi http://jci.me/92931

Filamin aggregates in muscle cells

Lymphatic endothelial cells

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Editor’s picks

Podoplanin marks a population of nonpathogenic Th17 cellsimmunology

Self-reactive Th17 cells have been implicated in a variety of autoimmune disorders. Recent evidence indicates that distinct subpopulations of Th17 cells with different functional properties develop in response to various inflamma-tory stimuli. Podoplanin-expressing Th17 cells have been identified in multiple mouse models of autoimmune inflammation; therefore, Alyssa Nylander and colleagues sought to characterize this population in humans. Unlike murine podoplanin-positive Th17 cells, those isolated from humans did not generate IL-17 — despite expression of canonical Th17 transcription factors — and exhibited upregulation of immunosuppressive and regulatory pathways. Exposure of human podoplanin-positive Th17 cells to high salt conditions, which promotes secretion of proinflammatory modulators, reduced podoplanin expression, while the podoplanin-binding ligand CLEC2 reduced IL-17 expression. Finally, evaluation of biopsies from patients with Th17-driven skin candidiasis revealed the presence of a podoplanin-positive T cell subset that did not produce IL-17 (see the accompanying image). Together, these data support podoplanin-expressing Th17 cells as a nonpathogenic population.

Podoplanin is a negative regulator of Th17 inflammationAlyssa N. Nylander, Gerald D. Ponath, Pierre-Paul Axisa, Mayyan Mubarak, Mary Tomayko, Vijay K. Kuchroo, David Pitt, and David A. Hafler http://jci.me/92321

Taking the Aire out of melanomaFor a small subset of patients with advanced melanoma, treatment with immune checkpoint inhibitors, which augment melanoma-targeting T cell activity, dramatically improves survival. It is not clear why the majority of patients show no benefit from checkpoint inhibition; however, it is possible that the melanoma-reactive T cell pool is limited. Pearl Bakhru, Meng-Lei Zhu, and colleagues questioned whether or not the autoimmune regulator (Aire), which has been shown to promote removal of T cells capable of targeting melanoma, influences checkpoint

inhibitor efficacy. In murine models of melanoma, Aire deficiency expanded the population of melanoma-reactive T cells and, in combination with checkpoint inhibition, slowed tumor growth and increased survival. Moreover, the presence of an Aire polymorphism in humans associated with melanoma protection improved responses to the checkpoint inhibitor anti–CTLA-4. Collectively, these results indicate that targeting Aire along with checkpoint inhibition may enhance antimelanoma responses.

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunityPearl Bakhru, Meng-Lei Zhu, Hsing-Hui Wang, Lee K. Hong, Imran Khan, Maria Mouchess, Ajay S. Gulati, Joshua Starmer, Yafei Hou, David Sailer, Sandra Lee, Fengmin Zhao, John M. Kirkwood, Stergios Moschos, Lawrence Fong, Mark S. Anderson, and Maureen A. Su http://jci.me/93265

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JCI Insight | Editor’s picks

infectious disease

Innate immune responses in children with malariaChildren with malaria present with a spectrum of diseases, ranging from asymptomatic infection to severe lethal disease, with host immune responses contributing to the clinical presentation. Katherine Dobbs and colleagues evaluated markers of inflammation and monocyte populations in Kenyan children who presented with acute uncomplicated malaria and reevaluated these parameters in the same children 6 weeks later. Acute malaria was associated with elevated proinflammatory cytokine levels and increased proportions of an activated intermediate monocyte population, both of which returned to levels similar to those seen in healthy, asymptomatic children from the same region. Monocytes from children with acute malaria exhibited impaired ability to phagocytize Plasmodium falciparum–infected erythrocytes compared with monocytes from the same children 6 weeks later. However, in a subset of these blood samples at 6 weeks, the children had asymptomatic infection and their monocytes continued to exhibit impaired phagocytic functions. This study sets the stage for future work to better understand how the observed changes in monocyte function affect disease severity.

Monocyte dysregulation and systemic inflammation during pediatric falciparum malariaKatherine R. Dobbs, Paula Embury, John Vulule, Peter S. Odada, Bruce A. Rosa, Makedonka Mitreva, James W. Kazura, and Arlene E. Dent http://jci.me/95352

c-PAP use reduces inflammation in obese subjects with sleep apneaAdipose tissue inflammation in obesity is linked to adverse outcomes, including type 2 diabetes. Obstructive sleep apnea (OSA) disrupts breathing, resulting in chronic intermittent hypoxia (CIH), and recent studies suggest that CIH increases adipose tissue inflammation. Sebastio Perrini and colleagues evaluated adipose tissue from obese individuals with and without OSA before and after weight loss intervention. Additionally, compliance with continuous positive airway pressure (c-PAP) usage was determined for those with OSA to reduce CIH. There was no notable difference in markers of inflammation in adipose tissue from obese individuals with and without OSA at baseline. While all individuals lost weight following the intervention, only obese individuals with OSA who adhered to c-PAP usage showed signs of reduced adipose and systemic inflammation. These results indicate that CIH does not exacerbate obesity-associated inflammation and that reduction of CIH in obese subjects with OSA is beneficial.

Correction of intermittent hypoxia reduces inflammation in obese subjects with obstructive sleep apneaSebastio Perrini, Angelo Cignarelli, Vitaliano Nicola Quaranta, Vito Antonio Falcone, Stella Kounaki, Stefania Porro, Alessandro Ciavarella, Romina Ficarella, Maria Barbaro, Valentina Annamaria Genchi, Pasquale Nigro, Pierluigi Carratù, Annalisa Natalicchio, Luigi Laviola, Onofrio Resta, and Francesco Giorgino http://jci.me/94379

metabolism

nephrology

Mouse model for following kidney injury progressionAcute injury to the kidney increases the risk of chronic kidney disease and progression to end-organ failure; however, little is known about the drivers of this process. Jing Liu, Sanjeev Kumar, and colleagues developed a murine model of ischemia/reperfusion injury that allowed them to characterize the molecular events that occur over a 12-month period during the transition from acute injury to chronic kidney disease. Using a combination of RNA sequencing, histological staining, and characterization of targeted gene activity, the authors determined that there are distinct phases of renal response that correlate with expression of specific gene sets. Moreover, comparison of early- and late-phase gene sets from the mouse model with human data sets revealed a conservation of the transcriptional response following injury. These results provide important insight into the events that occur during the transition from acute to chronic kidney disease and a model for further in-depth analysis of this process. The accompanying image shows histological changes in the kidney over a 12-month period after ischemia/reperfusion.

Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusionJing Liu, Sanjeev Kumar, Egor Dolzhenko, Gregory F. Alvarado, Jinjin Guo, Can Lu, Yibu Chen, Meng Li, Mark C. Dessing, Riana K. Parvez, Pietro E. Cippà, A. Michaela Krautzberger, Gohar Saribekyan, Andrew D. Smith, and Andrew P. McMahon http://jci.me/94716

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JCI Insight | Editor’s picks

A D V E R T I S E M E N T

pulm0nology

Characterization of cystic fibrosis–associated airway smooth muscle dysfunctionSome individuals with cystic fibrosis (CF) develop asthma-like disease, though, it is unclear whether this manifestation is due to CFTR dysfunction. Recently, alterations in airway smooth muscle function have been reported in porcine CF models, prior to the onset of airway inflammation. Daniel Cook and colleagues revealed intrinsic CF-associated changes in airway smooth muscle by comparing the airway smooth muscle transcriptome of newborn WT pigs and newborn CTFR-deficient CF pigs. Additionally, a small-molecule inhibitor of proline-rich tyrosine kinase 2 (PYK2), which was phosphorylated to a greater extent in CF, corrected alterations in airway smooth muscle contraction in both isolated CF airway smooth muscle tissue and in methacholine-treated mice (accompanying image). Together, these results implicate airway smooth muscle as a therapeutic target for CF asthma.

CF airway smooth muscle transcriptome reveals a role for PYK2Daniel P. Cook, Ryan J. Adam, Keyan Zarei, Benjamin Deonovic, Mallory R. Stroik, Nicholas D. Gansemer, David K. Meyerholz, Kin Fai Au, and David A. Stoltz http://jci.me/95332

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Current articles

Adult cardiomyocytes

Ventricular muscle

Endocortical remodeling in bone

Prevention of breast cancer skeletal metastases with parathyroid hormoneSrilatha Swami, Joshua Johnson, Lance A. Bettinson, Takaharu Kimura, Hui Zhu, Megan A. Albertelli, Rachelle W. Johnson, and Joy Y. Wu http://jci.me/90874

Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interfaceJianqin Wei, Shaurya Joshi, Svetlana Speransky, Christopher Crowley, Nimanthi Jayathilaka, Xiao Lei, Yongqing Wu, David Gai, Sumit Jain, Michael Hoosien, Yan Gao, Lin Chen, and Nanette H. Bishopric http://jci.me/91068

Endothelium-derived extracellular vesicles promote splenic monocyte mobilization in myocardial infarction

Naveed Akbar, Janet E. Digby, Thomas J. Cahill, Abhijeet N. Tavare, Alastair L. Corbin, Sushant Saluja, Sam Dawkins, Laurienne Edgar, Nadiia Rawlings, Klemen Ziberna, Eileen McNeill, Oxford Acute Myocardial Infarction (OxAMI) Study, Errin Johnson, Alaa A. Aljabali, Rebecca A. Dragovic, Mala Rohling, T. Grant Belgard, Irina A. Udalova, David R. Greaves, Keith M. Channon, Paul R. Riley, Daniel C. Anthony, and Robin P. Choudhury http://jci.me/93344

IL-23R–activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunityPriscilla W. Lee, Alan J. Smith, Yuhong Yang, Amanda J. Selhorst, Yue Liu, Michael K. Racke, and Amy E. Lovett-Racke http://jci.me/91663

Podoplanin is a negative regulator of Th17 inflammation p. 10Alyssa N. Nylander, Gerald D. Ponath, Pierre-Paul Axisa, Mayyan Mubarak, Mary Tomayko, Vijay K. Kuchroo, David Pitt, and David A. Hafler http://jci.me/92321

Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathyRuya Liu, Jeongkyung Lee, Byung S. Kim, Qiongling Wang, Samuel K. Buxton, Nikhil Balasubramanyam, Jean J. Kim, Jianrong Dong, Aijun Zhang, Shumin Li, Anisha A. Gupte, Dale J. Hamilton, James F. Martin, George G. Rodney, Cristian Coarfa, Xander H.T. Wehrens, Vijay K. Yechoor, and Mousumi Moulik http://jci.me/93343

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial functionLeroy C. Joseph, Dimitra Kokkinaki, Mesele-Christina Valenti, Grace J. Kim, Emanuele Barca, Dhanendra Tomar, Nicholas E. Hoffman, Prakash Subramanyam, Henry M. Colecraft, Michio Hirano, Adam J. Ratner, Muniswamy Madesh, Konstantinos Drosatos, and John P. Morrow http://jci.me/94248

Stereotyped antibody responses target posttranslationally modified gluten in celiac diseaseOmri Snir, Xi Chen, Moriah Gidoni, M. Fleu du Pré, Yuguang Zhao, Øyvind Steinsbø, Knut E.A. Lundin, Gur Yaari, and Ludvig M. Sollid http://jci.me/93961

Old age causes de novo intracortical bone remodeling and porosity in miceMarilina Piemontese, Maria Almeida, Alexander G. Robling, Ha-Neui Kim, Jinhu Xiong, Jeff D. Thostenson, Robert S. Weinstein, Stavros C. Manolagas, Charles A. O’Brien, and Robert L. Jilka http://jci.me/93771

Pharmacologic HIV-1 Nef blockade promotes CD8 T cell–mediated elimination of latently HIV-1–infected cells in vitro

Shariq Mujib, Aamir Saiyed, Saleh Fadel, Ardalan Bozorgzad, Nasra Aidarus, Feng Yun Yue, Erika Benko, Colin Kovacs, Lori A. Emert-Sedlak, Thomas E. Smithgall, and Mario A. Ostrowski http://jci.me/93684

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Current articles

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetesSandrine Levet, Julie Medina, Julie Joanou, Amandine Demolder, Nelly Queruel, Kevin Réant, Matthieu Normand, Marine Seffals, Julie Dimier, Raphaële Germi, Thomas Piofczyk, Jacques Portoukalian, Jean-Louis Touraine, and Hervé Perron http://jci.me/94387

Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravisPanos Stathopoulos, Aditya Kumar, Richard J. Nowak, and Kevin C. O’Connor http://jci.me/94263

Correction of intermittent hypoxia reduces inflammation in obese subjects with obstructive sleep apnea p. 11Sebastio Perrini, Angelo Cignarelli, Vitaliano Nicola Quaranta, Vito Antonio Falcone, Stella Kounaki, Stefania Porro, Alessandro Ciavarella, Romina Ficarella, Maria Barbaro, Valentina Annamaria Genchi, Pasquale Nigro, Pierluigi Carratù, Annalisa Natalicchio, Luigi Laviola, Onofrio Resta, and Francesco Giorgino http://jci.me/94379

Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune responseSudipta Das, Mahesh Raundhal, Jie Chen, Timothy B. Oriss, Rachael Huff, John V. Williams, Anuradha Ray, and Prabir Ray http://jci.me/94605

Wnt11 regulates cardiac chamber development and disease during perinatal maturationMarlin Touma, Xuedong Kang, Fuying Gao, Yan Zhao, Ashley A. Cass, Reshma Biniwale, Xinshu Xiao, Mansuoreh Eghbali, Giovanni Coppola, Brian Reemtsen, and Yibin Wang http://jci.me/94904

Human hepatic organoids for the analysis of human genetic diseasesYuan Guan, Dan Xu, Phillip M. Garfin, Ursula Ehmer, Melissa Hurwitz, Greg Enns, Sara Michie, Manhong Wu, Ming Zheng,

Toshihiko Nishimura, Julien Sage, and Gary Peltz http://jci.me/94954

The R213G polymorphism in SOD3 protects against allergic airway inflammationRohit Gaurav, Jason T. Varasteh, Michael R. Weaver, Sean R. Jacobson, Laura Hernandez-Lagunas, Qing Liu, Eva Nozik-Grayck, Hong Wei Chu, Rafeul Alam, Børge G. Nordestgaard, Camilla J. Kobylecki, Shoaib Afzal, Geoffrey L. Chupp, and Russell P. Bowler http://jci.me/95072

REV-ERBα ameliorates heart failure through transcription repressionLilei Zhang, Rongli Zhang, Chih-Liang Tien, Ricky E. Chan, Keiki Sugi, Chen Fu, Austin C. Griffin, Yuyan Shen, Thomas P. Burris, Xudong Liao, and Mukesh K. Jain http://jci.me/95177

A TCRα framework–centered codon shapes a biased T cell repertoire through direct MHC and CDR3β interactionsKristin Støen Gunnarsen, Lene Støkken Høydahl, Louise Fremgaard Risnes, Shiva Dahal-Koirala,

Ralf Stefan Neumann, Elin Bergseng, Terje Frigstad, Rahel Frick, M. Fleur du Pré, Bjørn Dalhus, Knut E.A. Lundin, Shuo-Wang Qiao, Ludvig M. Sollid, Inger Sandlie, and Geir Åge Løset http://jci.me/95193

CF airway smooth muscle transcriptome reveals a role for PYK2 p. 12Daniel P. Cook, Ryan J. Adam, Keyan Zarei, Benjamin Deonovic, Mallory R. Stroik, Nicholas D. Gansemer, David K. Meyerholz, Kin Fai Au, and David A. Stoltz http://jci.me/95332

Immune infiltrate in human pancreas

Developing cardiomyocytes

Intracardiac fibrosis

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Physiological adaptations to resistance exercise as a function of ageBethan E. Phillips, John P. Williams, Paul L. Greenhaff, Kenneth Smith, and Philip J. Atherton http://jci.me/95581

Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastasesNolan Priedigkeit, Rebecca J. Watters, Peter C. Lucas, Ahmed Basudan, Rohit Bhargava, William Horne, Jay K. Kolls, Zhou Fang, Margaret Q. Rosenzweig, Adam M. Brufsky, Kurt R. Weiss, Steffi Oesterreich, and Adrian V. Lee http://jci.me/95703

Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancerFumi Sato-Kaneko, Shiyin Yao, Alast Ahmadi, Shannon S. Zhang, Tadashi Hosoya, Megan M. Kaneda, Judith A. Varner, Minya Pu, Karen S. Messer, Cristiana Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Dennis A. Carson, Tomoko Hayashi, and Ezra E.W. Cohen http://jci.me/93397

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signalingPierre-Yves Jean-Charles, Samuel Mon-Wei Yu, Dennis Abraham, Reddy Peera Kommaddi, Lan Mao, Ryan T. Strachan, Zhu-Shan Zhang, Dawn E. Bowles, Leigh Brian, Jonathan A. Stiber, Stephen N. Jones, Walter J. Koch, Howard A. Rockman, and Sudha K. Shenoy http://jci.me/95998

Essential role of Kir5.1 channels in renal salt handling and blood pressure controlOleg Palygin, Vladislav Levchenko, Daria V. Ilatovskaya, Tengis S. Pavlov, Oleh M. Pochynyuk, Howard J. Jacob, Aron M. Geurts, Matthew R. Hodges, and Alexander Staruschenko http://jci.me/92331

L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor

Daiki Masukawa, Motokazu Koga, Anna Sezaki, Yuka Nakao, Yuji Kamikubo, Tatsuo Hashimoto, Yuki Okuyama-Oki, Aderemi Caleb Aladeokin, Fumio Nakamura, Utako Yokoyama, Hiromichi Wakui, Hiroshi Ichinose, Takashi Sakurai, Satoshi Umemura, Koichi Tamura, Yoshihiro Ishikawa, and Yoshio Goshima http://jci.me/90903

ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasisMingzhu Yin, Huanjiao Jenny Zhou, Jiqin Zhang, Caixia Lin, Hongmei Li, Xia Li, Yonghao Li, Haifeng Zhang, David G. Breckenridge, Weidong Ji, and Wang Min http://jci.me/91828

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical stormOlujimi A. Ajijola, Donald B. Hoover, Thomas M. Simerly, T. Christopher Brown, Jane Yanagawa, Reshma M. Biniwale, Jay M. Lee, Ali Sadeghi, Negar Khanlou, Jeffrey L. Ardell, and Kalyanam Shivkumar http://jci.me/94715

Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome

Anne-Lise Lecoq, Constantine A. Stratakis, Say Vienchareun, Ronan Chaligné, Lucie Tosca, Vianney Deméocq, Mirella Hage, Annabel Berthon, Fabio R. Faucz, Patrick Hanna, Hadrian-Gaël Boyer, Nicolas Servant, Sylvie Salenave, Gérard Tachdjian, Clovis Adam, Vanessa Benhamo, Eric Clauser, Anne Guiochon-Mantel, Jacques Young, Marc Lombès, Isabelle Bourdeau, Dominique Maiter, Antoine Tabarin, Jérôme Bertherat, Hervé Lefebvre, Wouter de Herder, Estelle Louiset, André Lacroix, Philippe Chanson, Jérôme Bouligand, and Peter Kamenický http://jci.me/92184

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity p. 10Pearl Bakhru, Meng-Lei Zhu, Hsing-Hui Wang, Lee K. Hong, Imran Khan, Maria Mouchess, Ajay S. Gulati, Joshua Starmer, Yafei Hou, David Sailer, Sandra Lee, Fengmin Zhao, John M. Kirkwood, Stergios Moschos, Lawrence Fong, Mark S. Anderson, and Maureen A. Su http://jci.me/93265

Tumor-infiltrating macrophages

Rodent kidney cortex

Stellate ganglia neurons

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JCI Insight | Current articles

Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion p. 11Jing Liu, Sanjeev Kumar, Egor Dolzhenko, Gregory F. Alvarado, Jinjin Guo, Can Lu, Yibu Chen, Meng Li, Mark C. Dessing, Riana K. Parvez, Pietro E. Cippà, A. Michaela Krautzberger, Gohar Saribekyan, Andrew D. Smith, and Andrew P. McMahon http://jci.me/94716

Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic targetsJason S. Knight, He Meng, Patrick Coit, Srilakshmi Yalavarthi, Gautam Sule, Alex A. Gandhi, Robert C. Grenn, Levi F. Mazza, Ramadan A. Ali, Paul Renauer, Jonathan D. Wren, Paula L. Bockenstedt, Hui Wang, Daniel T. Eitzman, and Amr H. Sawalha http://jci.me/93897

Reversible retinal vessel closure from VEGF-induced leukocyte pluggingYuanyuan Liu, Jikui Shen, Seth D. Fortmann, Jiangxia Wang, Dietmar Vestweber, and Peter A. Campochiaro http://jci.me/95530

Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healingKristine Y. DeLeon-Pennell, Rugmani Padmanabhan Iyer, Osasere K. Ero, Courtney A. Cates, Elizabeth R. Flynn,

Presley L. Cannon, Mira Jung, De’Aries Shannon, Michael R. Garrett, William Buchanan, Michael E. Hall, Yonggang Ma, and Merry L. Lindsey http://jci.me/94207

VISTA.COMP — an engineered checkpoint receptor agonist that potently suppresses T cell–mediated immune responsesAaron Prodeus, Aws Abdul-Wahid, Amanda Sparkes, Nicholas W. Fischer, Marzena Cydzik, Nicholas Chiang, Mays Alwash, Alessandra Ferzoco, Nathalie Vacaresse, Michael Julius, Reginald M. Gorczysnki, and Jean Gariépy http://jci.me/94308

Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria p. 11Katherine R. Dobbs, Paula Embury, John Vulule, Peter S. Odada, Bruce A. Rosa, Makedonka Mitreva, James W. Kazura, and Arlene E. Dent http://jci.me/95352

Functional correction of dystrophin actin binding domain mutations by genome editingViktoriia Kyrychenko, Sergii Kyrychenko, Malte Tiburcy, John M. Shelton, Chengzu Long, Jay W. Schneider, Wolfram-Hubertus Zimmermann, Rhonda Bassel-Duby, and Eric N. Olson http://jci.me/95918

A type of human skin dendritic cell marked by CD5 is associated with the development of inflammatory skin disease

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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

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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

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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

Fumihiko Urano

Charles P. Venditti

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