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Richard a flavell

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https://www.readbyqxmd.com/read/29109123/a-protective-function-of-il-22bp-in-ischemia-reperfusion-and-acetaminophen-induced-liver-injury
#1
Dörte Kleinschmidt, Anastasios D Giannou, Heather M McGee, Jan Kempski, Babett Steglich, Francis Jessica Huber, Thomas Michael Ernst, Ahmad Mustafa Shiri, Claudia Wegscheid, Elena Tasika, Peter Hübener, Philipp Huber, Tanja Bedke, Niklas Steffens, Theodora Agalioti, Tobias Fuchs, Jill Noll, Hannelore Lotter, Gisa Tiegs, Ansgar W Lohse, Jonathan H Axelrod, Eithan Galun, Richard A Flavell, Nicola Gagliani, Samuel Huber
Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury...
November 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29078283/humanized-mouse-model-supports-development-function-and-tissue-residency-of-human-natural-killer-cells
#2
Dietmar Herndler-Brandstetter, Liang Shan, Yi Yao, Carmen Stecher, Valerie Plajer, Melanie Lietzenmayer, Till Strowig, Marcel R de Zoete, Noah W Palm, Jie Chen, Catherine A Blish, Davor Frleta, Cagan Gurer, Lynn E Macdonald, Andrew J Murphy, George D Yancopoulos, Ruth R Montgomery, Richard A Flavell
Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2(-/-)Il2rg(-/-) background (SRG-15)...
October 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29069606/distinct-microbial-communities-trigger-colitis-development-upon-intestinal-barrier-damage-via-innate-or-adaptive-immune-cells
#3
Urmi Roy, Eric J C Gálvez, Aida Iljazovic, Till Robin Lesker, Adrian J Błażejewski, Marina C Pils, Ulrike Heise, Samuel Huber, Richard A Flavell, Till Strowig
Inflammatory bowel disease comprises a group of heterogeneous diseases characterized by chronic and relapsing mucosal inflammation. Alterations in microbiota composition have been proposed to contribute to disease development, but no uniform signatures have yet been identified. Here, we compare the ability of a diverse set of microbial communities to exacerbate intestinal inflammation after chemical damage to the intestinal barrier. Strikingly, genetically identical wild-type mice differing only in their microbiota composition varied strongly in their colitis susceptibility...
October 24, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045905/transcriptional-reprogramming-during-effector-to-memory-transition-renders-cd4-t-cells-permissive-for-latent-hiv-1-infection
#4
Liang Shan, Kai Deng, Hongbo Gao, Sifei Xing, Adam A Capoferri, Christine M Durand, S Alireza Rabi, Gregory M Laird, Michelle Kim, Nina N Hosmane, Hung-Chih Yang, Hao Zhang, Joseph B Margolick, Linghua Li, Weiping Cai, Ruian Ke, Richard A Flavell, Janet D Siliciano, Robert F Siliciano
The latent reservoir for HIV-1 in resting memory CD4(+) T cells is the major barrier to curing HIV-1 infection. Studies of HIV-1 latency have focused on regulation of viral gene expression in cells in which latent infection is established. However, it remains unclear how infection initially becomes latent. Here we described a unique set of properties of CD4(+) T cells undergoing effector-to-memory transition including temporary upregulation of CCR5 expression and rapid downregulation of cellular gene transcription...
October 17, 2017: Immunity
https://www.readbyqxmd.com/read/28930674/a-protein-scaffold-coordinates-src-mediated-jnk-activation-in-response-to-metabolic-stress
#5
Shashi Kant, Claire L Standen, Caroline Morel, Dae Young Jung, Jason K Kim, Wojciech Swat, Richard A Flavell, Roger J Davis
Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA) activation of a non-receptor tyrosine kinase (SRC)-dependent cJun NH2-terminal kinase (JNK) signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28930659/group-1-innate-lymphoid-cell-lineage-identity-is-determined-by-a-cis-regulatory-element-marked-by-a-long-non-coding-rna
#6
Walter K Mowel, Sam J McCright, Jonathan J Kotzin, Magalie A Collet, Asli Uyar, Xin Chen, Alexandra DeLaney, Sean P Spencer, Anthony T Virtue, EnJun Yang, Alejandro Villarino, Makoto Kurachi, Margaret C Dunagin, Gretchen Harms Pritchard, Judith Stein, Cynthia Hughes, Diogo Fonseca-Pereira, Henrique Veiga-Fernandes, Arjun Raj, Taku Kambayashi, Igor E Brodsky, John J O'Shea, E John Wherry, Loyal A Goff, John L Rinn, Adam Williams, Richard A Flavell, Jorge Henao-Mejia
Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28916785/selective-degradation-of-pu-1-during-autophagy-represses-the-differentiation-and-antitumour-activity-of-th9-cells
#7
Thaiz Rivera Vargas, Zhijian Cai, Yingying Shen, Magalie Dosset, Isis Benoit-Lizon, Tiffany Martin, Aurélie Roussey, Richard A Flavell, François Ghiringhelli, Lionel Apetoh
Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (TH9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into TH9 cells relative to Atg3- or Atg5-expressing control cells...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28898693/no-oxygen-no-glucose-no-problem-fatty-acid-catabolism-enhances-effector-cd8-tils
#8
COMMENT
Will Bailis, Justin A Shyer, Michael Chiorazzi, Richard A Flavell
The tumor microenvironment presents metabolic constraints to immunosurveiling cells. In this issue of Cancer Cell, Zhang et al. demonstrate that CD8(+) TILs reprogram under hypoxic and hypoglycemic conditions, regaining effector function by engaging fatty acid catabolism, which is promoted by fenofibrate and synergistic with immune checkpoint blockade therapy.
September 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28894001/intestinal-type-1-regulatory-t-cells-migrate-to-periphery-to-suppress-diabetogenic-t-cells-and-prevent-diabetes-development
#9
Hua Yu, Nicola Gagliani, Harumichi Ishigame, Samuel Huber, Shu Zhu, Enric Esplugues, Kevan C Herold, Li Wen, Richard A Flavell
Growing insight into the pathogenesis of autoimmune diseases and numerous studies in preclinical models highlights the potential of regulatory T cells to restore tolerance. By using non-obese diabetic (NOD) BDC2.5 TCR-transgenic (Tg), and IL-10 and Foxp3 double-reporter mice, we demonstrate that alteration of gut microbiota during cohousing experiments or treatment with anti-CD3 mAb significantly increase intestinal IL-10-producing type 1 regulatory T (Tr1) cells and decrease diabetes incidence. These intestinal antigen-specific Tr1 cells have the ability to migrate to the periphery via a variety of chemokine receptors such as CCR4, CCR5, and CCR7 and to suppress proliferation of Th1 cells in the pancreas...
September 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28813659/the-dna-methylcytosine-dioxygenase-tet2-sustains-immunosuppressive-function-of-tumor-infiltrating-myeloid-cells-to-promote-melanoma-progression
#10
Wen Pan, Shu Zhu, Kun Qu, Katrina Meeth, Jijun Cheng, Kaixin He, Hongdi Ma, Yan Liao, Xizhi Wen, Christine Roden, Zuzana Tobiasova, Zheng Wei, Jun Zhao, Jun Liu, Ji Zheng, Bo Guo, Sajid A Khan, Marcus Bosenberg, Richard A Flavell, Jun Lu
Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients and that this increased expression is dependent on an IL-1R-MyD88 pathway. Ablation of Tet2 in myeloid cells suppressed melanoma growth in vivo and shifted the immunosuppressive gene expression program in tumor-associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function...
August 15, 2017: Immunity
https://www.readbyqxmd.com/read/28792938/m-6-a-mrna-methylation-controls-t-cell-homeostasis-by-targeting-the-il-7-stat5-socs-pathways
#11
Hua-Bing Li, Jiyu Tong, Shu Zhu, Pedro J Batista, Erin E Duffy, Jun Zhao, Will Bailis, Guangchao Cao, Lina Kroehling, Yuanyuan Chen, Geng Wang, James P Broughton, Y Grace Chen, Yuval Kluger, Matthew D Simon, Howard Y Chang, Zhinan Yin, Richard A Flavell
N(6)-methyladenosine (m(6)A) is the most common and abundant messenger RNA modification, modulated by 'writers', 'erasers' and 'readers' of this mark. In vitro data have shown that m(6)A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m(6)A 'writer' protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation...
August 17, 2017: Nature
https://www.readbyqxmd.com/read/28746866/aim2-engages-active-but-unprocessed-caspase-1-to-induce-noncanonical-activation-of-the-nlrp3-inflammasome
#12
Larissa D Cunha, Alexandre L N Silva, Juliana M Ribeiro, Danielle P A Mascarenhas, Gustavo F S Quirino, Leonardo L Santos, Richard A Flavell, Dario S Zamboni
Inflammasomes are multimeric protein complexes that initiate inflammatory cascades. Their activation is a hallmark of many infectious or inflammatory diseases. Their composition and activity are specified by proinflammatory stimuli. For example, the NLRP3 inflammasome is activated in response to cell damage and K(+) efflux, whereas the AIM2 inflammasome is activated in response to cytosolic DNA. We used Legionella pneumophila, an intracellular bacterial pathogen that activates multiple inflammasomes, to elucidate the molecular mechanisms regulating inflammasome activation during infection...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28670480/long-term-consumption-of-caffeine-free-high-sucrose-cola-beverages-aggravates-the-pathogenesis-of-eae-in-mice
#13
Guangchao Cao, Qian Wang, Wanjun Huang, Jiyu Tong, Dewei Ye, Yan He, Zonghua Liu, Xin Tang, Hao Cheng, Qiong Wen, Dehai Li, Hau-Tak Chau, Yiming Wen, Hui Zhong, Ziyu Meng, Hui Liu, Zhenzhou Wu, Liqing Zhao, Richard A Flavell, Hongwei Zhou, Aimin Xu, Hengwen Yang, Zhinan Yin
Epidemiological data provide strong evidence of dramatically increasing incidences of many autoimmune diseases in the past few decades, mainly in western and westernized countries. Recent studies clearly revealed that 'Western diet' increases the risk of autoimmune diseases at least partially via disrupting intestinal tight junctions and altering the construction and metabolites of microbiota. However, the role of high sucrose cola beverages (HSCBs), which are one of the main sources of added sugar in the western diet, is barely known...
2017: Cell Discovery
https://www.readbyqxmd.com/read/28636595/nlrp9b-inflammasome-restricts-rotavirus-infection-in-intestinal-epithelial-cells
#14
Shu Zhu, Siyuan Ding, Penghua Wang, Zheng Wei, Wen Pan, Noah W Palm, Yi Yang, Hua Yu, Hua-Bing Li, Geng Wang, Xuqiu Lei, Marcel R de Zoete, Jun Zhao, Yunjiang Zheng, Haiwei Chen, Yujiao Zhao, Kellie A Jurado, Ningguo Feng, Liang Shan, Yuval Kluger, Jun Lu, Clara Abraham, Erol Fikrig, Harry B Greenberg, Richard A Flavell
Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown...
June 29, 2017: Nature
https://www.readbyqxmd.com/read/28618267/enhancement-of-ifn%C3%AE-production-by-distinct-commensals-ameliorates-salmonella-induced-disease
#15
Sophie Thiemann, Nathiana Smit, Urmi Roy, Till Robin Lesker, Eric J C Gálvez, Julia Helmecke, Marijana Basic, Andre Bleich, Andrew L Goodman, Ulrich Kalinke, Richard A Flavell, Marc Erhardt, Till Strowig
The microbiota contributes to colonization resistance against invading pathogens by competing for metabolites, producing inhibitory substances, and priming protective immune responses. However, the specific commensal bacteria that promote host resistance and immune-mediated protection remain largely elusive. Using isogenic mouse lines with distinct microbiota profiles, we demonstrate that severity of disease induced by enteric Salmonella Typhimurium infection is strongly modulated by microbiota composition in individual lines...
June 14, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28614717/microbiota-normalization-reveals-that-canonical-caspase-1-activation-exacerbates-chemically-induced-intestinal-inflammation
#16
Adrian J Błażejewski, Sophie Thiemann, Alexander Schenk, Marina C Pils, Eric J C Gálvez, Urmi Roy, Ulrike Heise, Marcel R de Zoete, Richard A Flavell, Till Strowig
Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1(-/-) and Casp11(-/-) mice and rederived them into an enhanced barrier facility to standardize the microbiota...
June 13, 2017: Cell Reports
https://www.readbyqxmd.com/read/28606987/the-fate-and-lifespan-of-human-monocyte-subsets-in-steady-state-and-systemic-inflammation
#17
Amit A Patel, Yan Zhang, James N Fullerton, Lies Boelen, Anthony Rongvaux, Alexander A Maini, Venetia Bigley, Richard A Flavell, Derek W Gilroy, Becca Asquith, Derek Macallan, Simon Yona
In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition...
July 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28495875/macrophage-function-in-tissue-repair-and-remodeling-requires-il-4-or-il-13-with-apoptotic-cells
#18
Lidia Bosurgi, Y Grace Cao, Mar Cabeza-Cabrerizo, Andrea Tucci, Lindsey D Hughes, Yong Kong, Jason S Weinstein, Paula Licona-Limon, Edward T Schmid, Facundo Pelorosso, Nicola Gagliani, Joseph E Craft, Richard A Flavell, Sourav Ghosh, Carla V Rothlin
Tissue repair is a subset of a broad repertoire of interleukin-4 (IL-4)- and IL-13-dependent host responses during helminth infection. Here we show that IL-4 or IL-13 alone was not sufficient, but IL-4 or IL-13 together with apoptotic cells induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of anti-inflammatory and tissue repair genes in the lungs after helminth infection or in the gut after induction of colitis...
June 9, 2017: Science
https://www.readbyqxmd.com/read/28467424/an-image-processing-and-analysis-tool-for-identifying-and-analysing-complex-plant-root-systems-in-3d-soil-using-non-destructive-analysis-root1
#19
Richard J Flavel, Chris N Guppy, Sheikh M R Rabbi, Iain M Young
The objective of this study was to develop a flexible and free image processing and analysis solution, based on the Public Domain ImageJ platform, for the segmentation and analysis of complex biological plant root systems in soil from x-ray tomography 3D images. Contrasting root architectures from wheat, barley and chickpea root systems were grown in soil and scanned using a high resolution micro-tomography system. A macro (Root1) was developed that reliably identified with good to high accuracy complex root systems (10% overestimation for chickpea, 1% underestimation for wheat, 8% underestimation for barley) and provided analysis of root length and angle...
2017: PloS One
https://www.readbyqxmd.com/read/28323879/mir-181b-regulates-vascular-stiffness-age-dependently-in-part-by-regulating-tgf-%C3%AE-signaling
#20
Daijiro Hori, Brittany Dunkerly-Eyring, Yohei Nomura, Debjit Biswas, Jochen Steppan, Jorge Henao-Mejia, Hideo Adachi, Lakshmi Santhanam, Dan E Berkowitz, Charles Steenbergen, Richard A Flavell, Samarjit Das
BACKGROUND: Endothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family in vascular inflammation has been documented. Here we tested whether the miR-181 family can influence the pathogenesis of hypertension and vascular stiffening. METHODS AND RESULTS: qPCR data showed a significant decrease in miR-181b expression in the aorta of the older mice. Eight miR-181a1/b1-/- mice and wild types (C57BL6J:WT) were followed weekly for pulse wave velocity (PWV) and blood pressure measurements...
2017: PloS One
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