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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/29348198/interleukin-10-stiffens-the-heart
#1
Daniela Cihakova
Cardiac-resident macrophages are a diverse population of cells that have a critical role in the pathogenesis of heart failure. A new understanding of communication between macrophages and cardiac fibroblasts could lead to novel therapeutic strategies for heart failure with preserved ejection function.
January 18, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29343501/sequential-bmp7-tgf-%C3%AE-1-signaling-and-microbiota-instruct-mucosal-langerhans-cell-differentiation
#2
Tal Capucha, Noam Koren, Maria Nassar, Oded Heyman, Tsipora Nir, Maayan Levy, Gili Zilberman-Schapira, Katya Zelentova, Luba Eli-Berchoer, Martin Zenke, Thomas Hieronymus, Asaf Wilensky, Herve Bercovier, Eran Elinav, Björn E Clausen, Avi-Hai Hovav
Mucosal Langerhans cells (LCs) originate from pre-dendritic cells and monocytes. However, the mechanisms involved in their in situ development remain unclear. Here, we demonstrate that the differentiation of murine mucosal LCs is a two-step process. In the lamina propria, signaling via BMP7-ALK3 promotes translocation of LC precursors to the epithelium. Within the epithelium, TGF-β1 finalizes LC differentiation, and ALK5 is crucial to this process. Moreover, the local microbiota has a major impact on the development of mucosal LCs, whereas LCs in turn maintain mucosal homeostasis and prevent tissue destruction...
January 17, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29343500/cbf%C3%AE-2-controls-differentiation-of-and-confers-homing-capacity-to-prethymic-progenitors
#3
Mari Tenno, Satoshi Kojo, Divine-Fondzenyuy Lawir, Isabell Hess, Katsuyuki Shiroguchi, Takashi Ebihara, Takaho A Endo, Sawako Muroi, Rumi Satoh, Hiroshi Kawamoto, Thomas Boehm, Ichiro Taniuchi
Multipotent hematopoietic progenitors must acquire thymus-homing capacity to initiate T lymphocyte development. Despite its importance, the transcriptional program underlying this process remains elusive. Cbfβ forms transcription factor complexes with Runx proteins, and here we show that Cbfβ2, encoded by an RNA splice variant of the Cbfb gene, is essential for extrathymic differentiation of T cell progenitors. Furthermore, Cbfβ2 endows extrathymic progenitors with thymus-homing capacity by inducing expression of the principal thymus-homing receptor, Ccr9...
January 17, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29339450/cardiac-macrophages-promote-diastolic-dysfunction
#4
Maarten Hulsmans, Hendrik B Sager, Jason D Roh, María Valero-Muñoz, Nicholas E Houstis, Yoshiko Iwamoto, Yuan Sun, Richard M Wilson, Gregory Wojtkiewicz, Benoit Tricot, Michael T Osborne, Judy Hung, Claudio Vinegoni, Kamila Naxerova, David E Sosnovik, Michael R Zile, Amy D Bradshaw, Ronglih Liao, Ahmed Tawakol, Ralph Weissleder, Anthony Rosenzweig, Filip K Swirski, Flora Sam, Matthias Nahrendorf
Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29339449/targeting-irf3-as-a-yap-agonist-therapy-against-gastric-cancer
#5
Shi Jiao, Jingmin Guan, Min Chen, Wenjia Wang, Chuanchuan Li, Yugong Wang, Yunfeng Cheng, Zhaocai Zhou
The Hippo pathway plays a vital role in tissue homeostasis and tumorigenesis. The transcription factor IRF3 is essential for innate antiviral immunity. In this study, we discovered IRF3 as an agonist of Yes-associated protein (YAP). The expression of IRF3 is positively correlated with that of YAP and its target genes in gastric cancer; the expression of both IRF3 and YAP is up-regulated and prognosticates patient survival. IRF3 interacts with both YAP and TEAD4 in the nucleus to enhance their interaction, promoting nuclear translocation and activation of YAP...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29339448/development-of-intestinal-m-cells-and-follicle-associated-epithelium-is-regulated-by-traf6-mediated-nf-%C3%AE%C2%BAb-signaling
#6
Takashi Kanaya, Sayuri Sakakibara, Toshi Jinnohara, Masami Hachisuka, Naoko Tachibana, Shinya Hidano, Takashi Kobayashi, Shunsuke Kimura, Toshihiko Iwanaga, Tomoo Nakagawa, Tatsuro Katsuno, Naoya Kato, Taishin Akiyama, Toshiro Sato, Ifor R Williams, Hiroshi Ohno
M cells are located in the follicle-associated epithelium (FAE) that covers Peyer's patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell-associated molecules but is not sufficient to complete M cell differentiation...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29339447/guidance-of-super-enhancers-in-regulation-of-il-9-induction-and-airway-inflammation
#7
Xiang Xiao, Yihui Fan, Junhui Li, Xiaolong Zhang, Xiaohua Lou, Yaling Dou, Xiaomin Shi, Peixiang Lan, Yue Xiao, Laurie Minze, Xian Chang Li
Th9 cells are prominently featured in allergic lung inflammation, but the mechanism that regulates IL-9 induction in T helper cells remains poorly defined. Here we demonstrate that formation of super-enhancers (SEs) is critical in robust induction of IL-9 and that assembly of the Il9 SEs in Th cells requires OX40-triggered chromatin acetylation. Mechanistically, we found that OX40 costimulation induces RelB expression, which recruits the histone acetyltransferase p300 to the Il9 locus to catalyze H3K27 acetylation...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29339446/ontogeny-of-human-mucosal-associated-invariant-t-cells-and-related-t-cell-subsets
#8
Ghada Ben Youssef, Marie Tourret, Marion Salou, Liana Ghazarian, Véronique Houdouin, Stanislas Mondot, Yvonne Mburu, Marion Lambert, Saba Azarnoush, Jean-Sébastien Diana, Anne-Laure Virlouvet, Michel Peuchmaur, Thomas Schmitz, Jean-Hugues Dalle, Olivier Lantz, Valérie Biran, Sophie Caillat-Zucman
Mucosal-associated invariant T (MAIT) cells are semi-invariant Vα7.2+ CD161highCD4- T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied Vα7.2+ CD161high T cell and related subset levels in infancy and after cord blood transplantation. We show that Vα7.2+ and Vα7.2- CD161high T cells are generated early during gestation and likely share a common prenatal developmental program...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29339445/bile-acids-in-glucose-metabolism-in-health-and-disease
#9
REVIEW
Hagit Shapiro, Aleksandra A Kolodziejczyk, Daniel Halstuch, Eran Elinav
Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut microbiome configuration...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29339444/light-hvem-signaling-in-keratinocytes-controls-development-of-dermatitis
#10
Rana Herro, Jr-Wen Shui, Sonja Zahner, Daniel Sidler, Yuko Kawakami, Toshiaki Kawakami, Koji Tamada, Mitchell Kronenberg, Michael Croft
Dermatitis is often associated with an allergic reaction characterized by excessive type 2 responses leading to epidermal acanthosis, hyperkeratosis, and dermal inflammation. Although factors like IL-4, IL-13, and thymic stromal lymphopoietin (TSLP) are thought to be instrumental for the development of this type of skin disorder, other cytokines may be critical. Here, we show that the tumor necrosis factor (TNF) superfamily protein LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes) is required for experimental atopic dermatitis, and LIGHT directly controls keratinocyte hyperplasia, and production of periostin, a matricellular protein that contributes to the clinical features of atopic dermatitis as well as other skin diseases such as scleroderma...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29339443/immune-system-the-seventh-sense
#11
REVIEW
Jonathan Kipnis
The brain is our computing machine that integrates stimuli from the environment and orchestrates responses to these stimuli. Here, I propose that the defining role of the immune system is to sense microorganisms and to inform the brain about them.
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29326381/b1a-b-cells-require-autophagy-for-metabolic-homeostasis-and-self-renewal
#12
Alexander J Clarke, Thomas Riffelmacher, Daniel Braas, Richard J Cornall, Anna Katharina Simon
Specific metabolic programs are activated by immune cells to fulfill their functional roles, which include adaptations to their microenvironment. B1 B cells are tissue-resident, innate-like B cells. They have many distinct properties, such as the capacity to self-renew and the ability to rapidly respond to a limited repertoire of epitopes. The metabolic pathways that support these functions are unknown. We show that B1 B cells are bioenergetically more active than B2 B cells, with higher rates of glycolysis and oxidative phosphorylation, and depend on glycolysis...
January 11, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29321225/humanized-trem2-mice-reveal-microglia-intrinsic-and-extrinsic-effects-of-r47h-polymorphism
#13
Wilbur M Song, Satoru Joshita, Yingyue Zhou, Tyler K Ulland, Susan Gilfillan, Marco Colonna
Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown...
January 10, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29305396/correction-the-immunology-of-hypertension
#14
Allison E Norlander, Meena S Madhur, David G Harrison
No abstract text is available yet for this article.
January 5, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29305395/ablation-of-endothelial-vegfr1-improves-metabolic-dysfunction-by-inducing-adipose-tissue-browning
#15
Takahiro Seki, Kayoko Hosaka, Carina Fischer, Sharon Lim, Patrik Andersson, Mitsuhiko Abe, Hideki Iwamoto, Yanyan Gao, Xinsheng Wang, Guo-Hua Fong, Yihai Cao
Angiogenesis plays an instrumental role in the modulation of adipose tissue mass and metabolism. Targeting adipose vasculature provides an outstanding opportunity for treatment of obesity and metabolic disorders. Here, we report the physiological functions of VEGFR1 in the modulation of adipose angiogenesis, obesity, and global metabolism. Pharmacological inhibition and genetic deletion of endothelial VEGFR1 augmented adipose angiogenesis and browning of subcutaneous white adipose tissue, leading to elevated thermogenesis...
January 5, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29301866/functional-and-clinical-relevance-of-vla-4-cd49d-cd29-in-ibrutinib-treated-chronic-lymphocytic-leukemia
#16
Erika Tissino, Dania Benedetti, Sarah E M Herman, Elisa Ten Hacken, Inhye E Ahn, Kari G Chaffee, Francesca Maria Rossi, Michele Dal Bo, Pietro Bulian, Riccardo Bomben, Elisabeth Bayer, Andrea Härzschel, Julia Christine Gutjahr, Massimiliano Postorino, Enrico Santinelli, Ayed Ayed, Francesco Zaja, Annalisa Chiarenza, Gabriele Pozzato, Alexandre Chigaev, Larry A Sklar, Jan A Burger, Alessandra Ferrajoli, Tait D Shanafelt, Adrian Wiestner, Giovanni Del Poeta, Tanja Nicole Hartmann, Valter Gattei, Antonella Zucchetto
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells...
January 4, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29282254/continuous-activity-of-foxo1-is-required-to-prevent-anergy-and-maintain-the-memory-state-of-cd8-t-cells
#17
Arnaud Delpoux, Rodrigo Hess Michelini, Shilpi Verma, Chen-Yen Lai, Kyla D Omilusik, Daniel T Utzschneider, Alec J Redwood, Ananda W Goldrath, Chris A Benedict, Stephen M Hedrick
Upon infection with an intracellular pathogen, cytotoxic CD8+ T cells develop diverse differentiation states characterized by function, localization, longevity, and the capacity for self-renewal. The program of differentiation is determined, in part, by FOXO1, a transcription factor known to integrate extrinsic input in order to specify survival, DNA repair, self-renewal, and proliferation. At issue is whether the state of T cell differentiation is specified by initial conditions of activation or is actively maintained...
December 27, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29282253/maturation-of-hematopoietic-stem-cells-from-prehematopoietic-stem-cells-is-accompanied-by-up-regulation-of-pd-l1
#18
Joanna Tober, Marijke M W Maijenburg, Yan Li, Long Gao, Brandon K Hadland, Peng Gao, Kodai Minoura, Irwin D Bernstein, Kai Tan, Nancy A Speck
Hematopoietic stem cells (HSCs) mature from pre-HSCs that originate in the major arteries of the embryo. To identify HSCs from in vitro sources, it will be necessary to refine markers of HSCs matured ex vivo. We purified and compared the transcriptomes of pre-HSCs, HSCs matured ex vivo, and fetal liver HSCs. We found that HSC maturation in vivo or ex vivo is accompanied by the down-regulation of genes involved in embryonic development and vasculogenesis, and up-regulation of genes involved in hematopoietic organ development, lymphoid development, and immune responses...
December 27, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29282252/iron-modulation-of-erythropoiesis-is-associated-with-scribble-mediated-control-of-the-erythropoietin-receptor
#19
Shadi Khalil, Lorrie Delehanty, Stephen Grado, Maja Holy, Zollie White, Katie Freeman, Ryo Kurita, Yukio Nakamura, Grant Bullock, Adam Goldfarb
Iron-restricted human anemias are associated with the acquisition of marrow resistance to the hematopoietic cytokine erythropoietin (Epo). Regulation of Epo responsiveness by iron availability serves as the basis for intravenous iron therapy in anemias of chronic disease. Epo engagement of its receptor normally promotes survival, proliferation, and differentiation of erythroid progenitors. However, Epo resistance caused by iron restriction selectively impairs proliferation and differentiation while preserving viability...
December 27, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29282251/%C3%AE-%C3%AE-t-cells-provide-the-early-source-of-ifn-%C3%AE-to-aggravate-lesions-in-spinal-cord-injury
#20
Guodong Sun, Shuxian Yang, Guangchao Cao, Qianghua Wang, Jianlei Hao, Qiong Wen, Zhizhong Li, Kwok-Fai So, Zonghua Liu, Sufang Zhou, Yongxiang Zhao, Hengwen Yang, Libing Zhou, Zhinan Yin
Immune responses and neuroinflammation are critically involved in spinal cord injury (SCI). γδ T cells, a small subset of T cells, regulate the inflammation process in many diseases, yet their function in SCI is still poorly understood. In this paper, we demonstrate that mice deficient in γδ T cells (TCRδ-/- ) showed improved functional recovery after SCI. γδ T cells are detected at the lesion sites within 24 hours after injury and are predominantly of the Vγ4 subtype and express the inflammatory cytokine IFN-γ...
December 27, 2017: Journal of Experimental Medicine
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