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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/29789388/tissue-resident-macrophages-in-the-intestine-are-long-lived-and-defined-by-tim-4-and-cd4-expression
#1
Tovah N Shaw, Stephanie A Houston, Kelly Wemyss, Hayley M Bridgeman, Thomas A Barbera, Tamsin Zangerle-Murray, Patrick Strangward, Amanda J L Ridley, Ping Wang, Samira Tamoutounour, Judith E Allen, Joanne E Konkel, John R Grainger
A defining feature of resident gut macrophages is their high replenishment rate from blood monocytes attributed to tonic commensal stimulation of this site. In contrast, almost all other tissues contain locally maintained macrophage populations, which coexist with monocyte-replenished cells at homeostasis. In this study, we identified three transcriptionally distinct mouse gut macrophage subsets that segregate based on expression of Tim-4 and CD4. Challenging current understanding, Tim-4+ CD4+ gut macrophages were found to be locally maintained, while Tim-4- CD4+ macrophages had a slow turnover from blood monocytes; indeed, Tim-4- CD4- macrophages were the only subset with the high monocyte-replenishment rate currently attributed to gut macrophages...
May 22, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29773644/bhlhe40-is-an-essential-repressor-of-il-10-during-mycobacterium-tuberculosis-infection
#2
Jeremy P Huynh, Chih-Chung Lin, Jacqueline M Kimmey, Nicholas N Jarjour, Elizabeth A Schwarzkopf, Tara R Bradstreet, Irina Shchukina, Oleg Shpynov, Casey T Weaver, Reshma Taneja, Maxim N Artyomov, Brian T Edelson, Christina L Stallings
The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis ( Mtb ) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ...
May 17, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29773643/the-transcription-factor-bhlhe40-is-a-switch-of-inflammatory-versus-antiinflammatory-th1-cell-fate-determination
#3
Fang Yu, Suveena Sharma, Dragana Jankovic, Rama Krishna Gurram, Pan Su, Gangqing Hu, Rao Li, Sadiye Rieder, Keji Zhao, Bing Sun, Jinfang Zhu
Type 1 T helper (Th1) cells play a critical role in host defense against intracellular pathogens and in autoimmune diseases by producing a key inflammatory cytokine interferon (IFN)-γ; some Th1 cells can also be antiinflammatory through producing IL-10. However, the molecular switch for regulating the differentiation of inflammatory and antiinflammatory Th1 cells is still elusive. Here, we show that Bhlhe40 -deficient CD4 Th1 cells produced less IFN-γ but substantially more IL-10 than wild-type Th1 cells both in vitro and in vivo...
May 17, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29773642/correction-peroxisome-proliferator-activated-receptor-ppar-%C3%AE-expression-in-t-cells-mediates-gender-differences-in-development-of-t-cell-mediated-autoimmunity
#4
Shannon E Dunn, Shalina S Ousman, Raymond A Sobel, Luis Zuniga, Sergio E Baranzini, Sawsan Youssef, Andrea Crowell, John Loh, Jorge Oksenberg, Lawrence Steinman
No abstract text is available yet for this article.
May 17, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29773641/il1rap-potentiates-multiple-oncogenic-signaling-pathways-in-aml
#5
Kelly Mitchell, Laura Barreyro, Tihomira I Todorova, Samuel J Taylor, Iléana Antony-Debré, Swathi-Rao Narayanagari, Luis A Carvajal, Joana Leite, Zubair Piperdi, Gopichand Pendurti, Ioannis Mantzaris, Elisabeth Paietta, Amit Verma, Kira Gritsman, Ulrich Steidl
The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability...
May 17, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29769249/spatial-distribution-and-function-of-t-follicular-regulatory-cells-in-human-lymph-nodes
#6
Ismail Sayin, Andrea J Radtke, Laura A Vella, Wenjie Jin, E John Wherry, Marcus Buggert, Michael R Betts, Ramin S Herati, Ronald N Germain, David H Canaday
T follicular regulatory (Tfr) cells are a population of CD4+ T cells that express regulatory T cell markers and have been shown to suppress humoral immunity. However, the precise mechanisms and location of Tfr-mediated suppression in the lymph node (LN) microenvironment are unknown. Using highly multiplexed quantitative imaging and functional assays, we examined the spatial distribution, suppressive function, and preferred interacting partners of Tfr cells in human mesenteric LNs. We find that the majority of Tfr cells express low levels of PD-1 and reside at the border between the T cell zone and B cell follicle, with very few found in the germinal centers (GCs)...
May 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29769248/targeting-tumor-cell-plasticity-by-combined-inhibition-of-notch-and-mapk-signaling-in-colon-cancer
#7
Eva Marina Schmidt, Sebastian Lamprecht, Cristina Blaj, Christian Schaaf, Stefan Krebs, Helmut Blum, Heiko Hermeking, Andreas Jung, Thomas Kirchner, David Horst
In colorectal cancer, signaling pathways driving tumor progression are promising targets for systemic therapy. Besides WNT and MAPK signaling, activation of NOTCH signaling is found in most tumors. Here, we demonstrate that high NOTCH activity marks a distinct colon cancer cell subpopulation with low levels of WNT and MAPK activity and with a pronounced epithelial phenotype. Therapeutic targeting of MAPK signaling had limited effects on tumor growth and caused expansion of tumor cells with high NOTCH activity, whereas upon targeting NOTCH signaling, tumor cells with high MAPK activity prevailed...
May 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29764914/less-cholesterol-means-better-tumor-killing-for-cytotoxic-t9-cells
#8
Brad Griesenauer, Sophie Paczesny
In this issue, Ma et al. (https://doi.org/10.1084/jem.20171576) show that removal of cholesterol from CD8 T cells during type 9 differentiation increases their IL-9 production, persistence in vivo, and cytolytic function against tumors by preventing SUMOylation of liver X receptors.
May 15, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29743292/cholesterol-negatively-regulates-il-9-producing-cd8-t-cell-differentiation-and-antitumor-activity
#9
Xingzhe Ma, Enguang Bi, Chunjian Huang, Yong Lu, Gang Xue, Xing Guo, Aibo Wang, Maojie Yang, Jianfei Qian, Chen Dong, Qing Yi
CD8+ T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8+ or CD4+ T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo...
May 9, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29743291/-pten-deletion-in-luminal-cells-of-mature-prostate-induces-replication-stress-and-senescence-in-vivo
#10
Maxime Parisotto, Elise Grelet, Rana El Bizri, Yongyuan Dai, Julie Terzic, Doriane Eckert, Laetitia Gargowitsch, Jean-Marc Bornert, Daniel Metzger
Genetic ablation of the tumor suppressor PTEN in prostatic epithelial cells (PECs) induces cell senescence. However, unlike oncogene-induced senescence, no hyperproliferation phase and no signs of DNA damage response (DDR) were observed in PTEN -deficient PECs; PTEN loss-induced senescence (PICS) was reported to be a novel type of cellular senescence. Our study reveals that PTEN ablation in prostatic luminal epithelial cells of adult mice stimulates PEC proliferation, followed by a progressive growth arrest with characteristics of cell senescence...
May 9, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29739836/inhibition-of-pkc%C3%AE-reduces-amyloid-%C3%AE-levels-and-reverses-alzheimer-disease-phenotypes
#11
Ying Du, Yingjun Zhao, Chuan Li, Qiuyang Zheng, Jing Tian, Zhuyi Li, Timothy Y Huang, Wei Zhang, Huaxi Xu
β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aβ degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain...
May 8, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29739835/nucleoside-modified-mrna-vaccines-induce-potent-t-follicular-helper-and-germinal-center-b-cell-responses
#12
Norbert Pardi, Michael J Hogan, Martin S Naradikian, Kaela Parkhouse, Derek W Cain, Letitia Jones, M Anthony Moody, Hans P Verkerke, Arpita Myles, Elinor Willis, Celia C LaBranche, David C Montefiori, Jenna L Lobby, Kevin O Saunders, Hua-Xin Liao, Bette T Korber, Laura L Sutherland, Richard M Scearce, Peter T Hraber, István Tombácz, Hiromi Muramatsu, Houping Ni, Daniel A Balikov, Charles Li, Barbara L Mui, Ying K Tam, Florian Krammer, Katalin Karikó, Patricia Polacino, Laurence C Eisenlohr, Thomas D Madden, Michael J Hope, Mark G Lewis, Kelly K Lee, Shiu-Lok Hu, Scott E Hensley, Michael P Cancro, Barton F Haynes, Drew Weissman
T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates...
May 8, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29728441/inhibition-of-ugt8-suppresses-basal-like-breast-cancer-progression-by-attenuating-sulfatide-%C3%AE-v%C3%AE-5-axis
#13
Qianhua Cao, Xingyu Chen, Xuebiao Wu, Ruocen Liao, Panpan Huang, Yanjia Tan, Li Wang, Guoping Ren, Jian Huang, Chenfang Dong
Basal-like breast cancer (BLBC) is associated with a poor clinical outcome as a result of the few treatment options and poor therapeutic response. Here, we report that elevated expression of urine diphosphate-galactose ceramide galactosyltransferase (UGT8) specifically occurs in BLBC and predicts poor prognosis in breast cancer patients. UGT8 expression is transcriptionally up-regulated by Sox10, triggering the sulfatide biosynthetic pathway; increased sulfatide activates integrin αVβ5-mediated signaling that contributes to BLBC progression...
May 4, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29728440/peripheral-pdgfr%C3%AE-gp38-mesenchymal-cells-support-the-differentiation-of-fetal-liver-derived-ilc2
#14
Satoshi Koga, Katsuto Hozumi, Ken-Ichi Hirano, Masaki Yazawa, Tommy Terooatea, Aki Minoda, Takashi Nagasawa, Shigeo Koyasu, Kazuyo Moro
Group 2 innate lymphoid cells (ILC2s) are derived from common lymphoid progenitors (CLPs) via several specific precursors, and the transcription factors essential for ILC2 differentiation have been extensively studied. However, the external factors regulating commitment to the ILC lineage as well as the sites and stromal cells that constitute the optimal microenvironment for ILC2-specific differentiation are not fully defined. In this study, we demonstrate that three key external factors, the concentration of interleukin 7 (IL-7) and strength and duration of Notch signaling, coordinately determine the fate of CLP toward the T, B, or ILC lineage...
May 4, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29724786/autism-associated-neuroligin-4-mutation-selectively-impairs-glycinergic-synaptic-transmission-in-mouse-brainstem-synapses
#15
Bo Zhang, Ozgun Gokce, W Dylan Hale, Nils Brose, Thomas C Südhof
In human patients, loss-of-function mutations of the postsynaptic cell-adhesion molecule neuroligin-4 were repeatedly identified as monogenetic causes of autism. In mice, neuroligin-4 deletions caused autism-related behavioral impairments and subtle changes in synaptic transmission, and neuroligin-4 was found, at least in part, at glycinergic synapses. However, low expression levels precluded a comprehensive analysis of neuroligin-4 localization, and overexpression of neuroligin-4 puzzlingly impaired excitatory but not inhibitory synaptic function...
May 3, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29724785/p2y1-receptor-blockade-normalizes-network-dysfunction-and-cognition-in-an-alzheimer-s-disease-model
#16
Nicole Reichenbach, Andrea Delekate, Björn Breithausen, Kevin Keppler, Stefanie Poll, Theresa Schulte, Jan Peter, Monika Plescher, Jan N Hansen, Nelli Blank, Armin Keller, Martin Fuhrmann, Christian Henneberger, Annett Halle, Gabor C Petzold
Astrocytic hyperactivity is an important contributor to neuronal-glial network dysfunction in Alzheimer's disease (AD). We have previously shown that astrocyte hyperactivity is mediated by signaling through the P2Y1 purinoreceptor (P2Y1R) pathway. Using the APPPS1 mouse model of AD, we here find that chronic intracerebroventricular infusion of P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, as measured by in vivo two-photon microscopy, augments structural synaptic integrity, and preserves hippocampal long-term potentiation...
May 3, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29703731/dysregulation-of-sphingolipid-metabolism-contributes-to-bortezomib-induced-neuropathic-pain
#17
Katherine Stockstill, Timothy M Doyle, Xisheng Yan, Zhoumou Chen, Kali Janes, Joshua W Little, Kathryn Braden, Filomena Lauro, Luigino Antonio Giancotti, Caron Mitsue Harada, Ruchi Yadav, Wen Hua Xiao, Jack M Lionberger, William L Neumann, Gary J Bennett, Han-Rong Weng, Sarah Spiegel, Daniela Salvemini
The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain...
April 27, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29691302/repressing-the-repressor-ezh2-mediates-macrophage-activation
#18
Annette E Neele, Menno P J de Winther
In this issue of JEM , Zhang et al. (https://doi.org/10.1084/jem.20171417) show that the suppressive epigenetic enzyme Ezh2 is an important regulator of macrophage activation. The absence of Ezh2 leads to reduced cytokine secretion and suppresses macrophage-dependent disease development. They identify the antiinflammatory factor Socs3 as an important target for Ezh2 and thus show that regulation of suppressive histone modifications controls macrophage activation in disease.
April 24, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29685951/dual-therapy-for-a%C3%AE-amyloidosis-in-ad-a-successful-one-two-combo
#19
Tirth K Patel, David M Holtzman
In this issue, Chiang et al. (https://doi.org/10.1084/jem.20171484) make a notable contribution to Alzheimer disease (AD) therapeutics in a thorough and rigorous study demonstrating superior efficacy of dual therapy against Aβ in a mouse model of amyloid β deposition.
April 23, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29669741/shp-1-regulates-hematopoietic-stem-cell-quiescence-by-coordinating-tgf-%C3%AE-signaling
#20
Linjia Jiang, Xue Han, Jin Wang, Chen Wang, Xiaoqiang Sun, Jiayi Xie, Guojin Wu, Hiep Phan, Zhenguo Liu, ChengCheng Zhang, Meng Zhao, Xunlei Kang
Cell cycle quiescence is critical for hematopoietic stem cell (HSC) maintenance. TGF-β signaling in bone marrow niche has been identified in regulating HSC quiescence; however, the intrinsic regulatory mechanisms remain unclear. This study reports that Shp-1 knockout HSCs have attenuated quiescence and impaired long-term self-renewal. SHP-1-activated HSCs are surrounded by megakaryocytes, which regulate HSC quiescence by producing TGF-β1. Mechanistically, SHP-1 interacts with the immunoreceptor tyrosine-based inhibition motif on TGF-β receptor 1 and is critical for TGF-β signaling activation in HSCs...
April 18, 2018: Journal of Experimental Medicine
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