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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/28330905/secretogranin-iii-as-a-disease-associated-ligand-for-antiangiogenic-therapy-of-diabetic-retinopathy
#1
Michelle E LeBlanc, Weiwen Wang, Xiuping Chen, Nora B Caberoy, Feiye Guo, Chen Shen, Yanli Ji, Hong Tian, Hui Wang, Rui Chen, Wei Li
Diabetic retinopathy (DR) is a leading cause of vision loss with retinal vascular leakage and/or neovascularization. Current antiangiogenic therapy against vascular endothelial growth factor (VEGF) has limited efficacy. In this study, we applied a new technology of comparative ligandomics to diabetic and control mice for the differential mapping of disease-related endothelial ligands. Secretogranin III (Scg3) was discovered as a novel disease-associated ligand with selective binding and angiogenic activity in diabetic but not healthy vessels...
March 22, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28330904/autonomous-tnf-is-critical-for-in-vivo-monocyte-survival-in-steady-state-and-inflammation
#2
Yochai Wolf, Anat Shemer, Michal Polonsky, Mor Gross, Alexander Mildner, Simon Yona, Eyal David, Ki-Wook Kim, Tobias Goldmann, Ido Amit, Mathias Heikenwalder, Sergei Nedospasov, Marco Prinz, Nir Friedman, Steffen Jung
Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient for TNF or TNF receptors are outcompeted by their wild-type counterpart...
March 22, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28302646/eosinophil-derived-il-4-drives-progression-of-myocarditis-to-inflammatory-dilated-cardiomyopathy
#3
Nicola L Diny, G Christian Baldeviano, Monica V Talor, Jobert G Barin, SuFey Ong, Djahida Bedja, Allison G Hays, Nisha A Gilotra, Isabelle Coppens, Noel R Rose, Daniela Čiháková
Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in children and young adults. DCMi develops in up to 30% of myocarditis patients, but the mechanisms involved in disease progression are poorly understood. Patients with eosinophilia frequently develop cardiomyopathies. In this study, we used the experimental autoimmune myocarditis (EAM) model to determine the role of eosinophils in myocarditis and DCMi. Eosinophils were dispensable for myocarditis induction but were required for progression to DCMi...
March 16, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28302645/pd-l1-on-tumor-cells-is-sufficient-for-immune-evasion-in-immunogenic-tumors-and-inhibits-cd8-t-cell-cytotoxicity
#4
Vikram R Juneja, Kathleen A McGuire, Robert T Manguso, Martin W LaFleur, Natalie Collins, W Nicholas Haining, Gordon J Freeman, Arlene H Sharpe
It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity...
March 16, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28298456/microglial-complement-receptor-3-regulates-brain-a%C3%AE-levels-through-secreted-proteolytic-activity
#5
Eva Czirr, Nicholas A Castello, Kira I Mosher, Joseph M Castellano, Izumi V Hinkson, Kurt M Lucin, Bernat Baeza-Raja, Jae Kyu Ryu, Lulin Li, Sasha N Farina, Nadia P Belichenko, Frank M Longo, Katerina Akassoglou, Markus Britschgi, John R Cirrito, Tony Wyss-Coray
Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator...
March 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28292823/correction-annular-pip3-accumulation-controls-actin-architecture-and-modulates-cytotoxicity-at-the-immunological-synapse
#6
Audrey Le Floc'h, Yoshihiko Tanaka, Niels S Bantilan, Guillaume Voisinne, Grégoire Altan-Bonnet, Yoshinori Fukui, Morgan Huse
No abstract text is available yet for this article.
March 14, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28289053/vegf165-induced-vascular-permeability-requires-nrp1-for-abl-mediated-src-family-kinase-activation
#7
Alessandro Fantin, Anastasia Lampropoulou, Valentina Senatore, James T Brash, Claudia Prahst, Clemens A Lange, Sidath E Liyanage, Claudio Raimondi, James W Bainbridge, Hellmut G Augustin, Christiana Ruhrberg
The vascular endothelial growth factor (VEGF) isoform VEGF165 stimulates vascular growth and hyperpermeability. Whereas blood vessel growth is essential to sustain organ health, chronic hyperpermeability causes damaging tissue edema. By combining in vivo and tissue culture models, we show here that VEGF165-induced vascular leakage requires both VEGFR2 and NRP1, including the VEGF164-binding site of NRP1 and the NRP1 cytoplasmic domain (NCD), but not the known NCD interactor GIPC1. In the VEGF165-bound receptor complex, the NCD promotes ABL kinase activation, which in turn is required to activate VEGFR2-recruited SRC family kinases (SFKs)...
March 13, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28289052/correction-erbin-deficiency-links-stat3-and-tgf-%C3%AE-pathway-defects-with-atopy-in-humans
#8
J J Lyons, Y Liu, C A Ma, X Yu, M P O'Connell, M G Lawrence, Y Zhang, K Karpe, M Zhao, A M Siegel, K D Stone, C Nelson, N Jones, T DiMaggio, D N Darnell, E Mendoza-Caamal, L Orozco, J D Hughes, J McElwee, R J Hohman, P A Frischmeyer-Guerrerio, M E Rothenberg, A F Freeman, S M Holland, J D Milner
No abstract text is available yet for this article.
March 13, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28283535/correction-elp3-drives-wnt-dependent-tumor-initiation-and-regeneration-in-the-intestine
#9
Aurélie Ladang, Francesca Rapino, Lukas C Heukamp, Lars Tharun, Kateryna Shostak, Damien Hermand, Sylvain Delaunay, Iva Klevernic, Zheshen Jiang, Nicolas Jacques, Diane Jamart, Valérie Migeot, Alexandra Florin, Serkan Göktuna, Brigitte Malgrange, Owen J Sansom, Laurent Nguyen, Reinhard Büttner, Pierre Close, Alain Chariot
No abstract text is available yet for this article.
March 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28283534/pms2-and-uracil-dna-glycosylases-act-jointly-in-the-mismatch-repair-pathway-to-generate-ig-gene-mutations-at-a-t-base-pairs
#10
Giulia Girelli Zubani, Marija Zivojnovic, Annie De Smet, Olivier Albagli-Curiel, François Huetz, Jean-Claude Weill, Claude-Agnès Reynaud, Sébastien Storck
During somatic hypermutation (SHM) of immunoglobulin genes, uracils introduced by activation-induced cytidine deaminase are processed by uracil-DNA glycosylase (UNG) and mismatch repair (MMR) pathways to generate mutations at G-C and A-T base pairs, respectively. Paradoxically, the MMR-nicking complex Pms2/Mlh1 is apparently dispensable for A-T mutagenesis. Thus, how detection of U:G mismatches is translated into the single-strand nick required for error-prone synthesis is an open question. One model proposed that UNG could cooperate with MMR by excising a second uracil in the vicinity of the U:G mismatch, but it failed to explain the low impact of UNG inactivation on A-T mutagenesis...
March 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28280036/myeloid-derived-cullin-3-promotes-stat3-phosphorylation-by-inhibiting-ogt-expression-and-protects-against-intestinal-inflammation
#11
Xinghui Li, Zhibin Zhang, Lupeng Li, Wei Gong, Audrey J Lazenby, Benjamin J Swanson, Laura E Herring, John M Asara, Jeffrey D Singer, Haitao Wen
Signal transducer and activator of transcription 3 (STAT3) is a key mediator of intestinal inflammation and tumorigenesis. However, the molecular mechanism that modulates STAT3 phosphorylation and activation is not fully understood. Here, we demonstrate that modification of STAT3 with O-linked β-N-acetylglucosamine (O-GlcNAc) on threonine 717 (T717) negatively regulates its phosphorylation and targets gene expression in macrophages. We further found that cullin 3 (CUL3), a cullin family E3 ubiquitin ligase, down-regulates the expression of the O-GlcNAc transferase (OGT) and inhibits STAT3 O-GlcNAcylation...
March 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28270406/akr1b1-promotes-basal-like-breast-cancer-progression-by-a-positive-feedback-loop-that-activates-the-emt-program
#12
Xuebiao Wu, Xiaoli Li, Qiang Fu, Qianhua Cao, Xingyu Chen, Mengjie Wang, Jie Yu, Jingpei Long, Jun Yao, Huixin Liu, Danping Wang, Ruocen Liao, Chenfang Dong
Basal-like breast cancer (BLBC) is associated with high-grade, distant metastasis and poor prognosis. Elucidating the determinants of aggressiveness in BLBC may facilitate the development of novel interventions for this challenging disease. In this study, we show that aldo-keto reductase 1 member B1 (AKR1B1) overexpression highly correlates with BLBC and predicts poor prognosis in breast cancer patients. Mechanistically, Twist2 transcriptionally induces AKR1B1 expression, leading to nuclear factor κB (NF-κB) activation...
March 7, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28264883/inflammatory-monocytes-require-type-i-interferon-receptor-signaling-to-activate-nk-cells-via-il-18-during-a-mucosal-viral-infection
#13
Amanda J Lee, Branson Chen, Marianne V Chew, Nicole G Barra, Mira M Shenouda, Tina Nham, Nico van Rooijen, Manel Jordana, Karen L Mossman, Robert D Schreiber, Matthias Mack, Ali A Ashkar
The requirement of type I interferon (IFN) for natural killer (NK) cell activation in response to viral infection is known, but the underlying mechanism remains unclear. Here, we demonstrate that type I IFN signaling in inflammatory monocytes, but not in dendritic cells (DCs) or NK cells, is essential for NK cell function in response to a mucosal herpes simplex virus type 2 (HSV-2) infection. Mice deficient in type I IFN signaling, Ifnar(-/-) and Irf9(-/-) mice, had significantly lower levels of inflammatory monocytes, were deficient in IL-18 production, and lacked NK cell-derived IFN-γ...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28254948/p38-inhibition-provides-anti-dna-virus-immunity-by-regulation-of-usp21-phosphorylation-and-sting-activation
#14
Yunfei Chen, Lufan Wang, Jiali Jin, Yi Luan, Cong Chen, Yu Li, Hongshang Chu, Xinbo Wang, Guanghong Liao, Yue Yu, Hongqi Teng, Yanming Wang, Weijuan Pan, Lan Fang, Lujian Liao, Zhengfan Jiang, Xin Ge, Bin Li, Ping Wang
Stimulator of IFN genes (STING) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STING function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STING activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING...
March 2, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28250012/innate-immunity-to-rna-virus-is-regulated-by-temporal-and-reversible-sumoylation-of-rig-i-and-mda5
#15
Ming-Ming Hu, Chen-Yang Liao, Qing Yang, Xue-Qin Xie, Hong-Bing Shu
Sensing of viral RNA by the cytosolic receptors RIG-I and melanoma differentiation-associated gene 5 (MDA5) leads to innate antiviral response. How RIG-I and MDA5 are dynamically regulated in innate antiviral response is not well understood. Here, we show that TRIM38 positively regulates MDA5- and RIG-I-mediated induction of downstream genes and acts as a SUMO E3 ligase for their dynamic sumoylation at K43/K865 and K96/K888, respectively, before and after viral infection. The sumoylation of MDA5 and RIG-I suppresses their K48-linked polyubiquitination and degradation in uninfected or early-infected cells...
March 1, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28246125/zmpste24-defends-against-influenza-and-other-pathogenic-viruses
#16
Bishi Fu, Lingyan Wang, Shitao Li, Martin E Dorf
Zinc metallopeptidase STE24 (ZMPSTE24) is a transmembrane metalloprotease whose catalytic activity is critical for processing lamin A on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum. We now report ZMPSTE24 is a virus-specific effector that restricts enveloped RNA and DNA viruses, including influenza A, Zika, Ebola, Sindbis, vesicular stomatitis, cowpox, and vaccinia, but not murine leukemia or adenovirus. ZMPSTE24-mediated antiviral action is independent of protease activity...
February 28, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28232470/epithelial-fli1-deficiency-drives-systemic-autoimmunity-and-fibrosis-possible-roles-in-scleroderma
#17
Takehiro Takahashi, Yoshihide Asano, Koji Sugawara, Takashi Yamashita, Kouki Nakamura, Ryosuke Saigusa, Yohei Ichimura, Tetsuo Toyama, Takashi Taniguchi, Kaname Akamata, Shinji Noda, Ayumi Yoshizaki, Daisuke Tsuruta, Maria Trojanowska, Shinichi Sato
Systemic sclerosis (SSc), or scleroderma, is a multisystem autoimmune disorder characterized by vasculopathy and fibrosis in the skin and internal organs, most frequently in the esophagus and lungs. Hitherto, studies on SSc pathogenesis centered on immune cells, vascular cells, and fibroblasts. Although dysregulated keratinocytes in SSc have been recently reported, the contribution of epithelial cells to pathogenesis remains unexplored. In this study, we demonstrated the induction of SSc-like molecular phenotype in keratinocytes by gene silencing of transcription factor Friend leukemia virus integration 1 (Fli1), the deficiency of which is implicated in SSc pathogenesis...
February 23, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28104811/correction-in-vivo-ncl-targeting-affects-breast-cancer-aggressiveness-through-mirna-regulation
#18
Flavia Pichiorri, Dario Palmieri, Luciana De Luca, Jessica Consiglio, Jia You, Alberto Rocci, Tiffany Talabere, Claudia Piovan, Alessandro Lagana, Luciano Cascione, Jingwen Guan, Pierluigi Gasparini, Veronica Balatti, Gerard Nuovo, Vincenzo Coppola, Craig C Hofmeister, Guido Marcucci, John C Byrd, Stefano Volinia, Charles L Shapiro, Michael A Freitas, Carlo M Croce
No abstract text is available yet for this article.
January 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28232471/distinct-populations-of-inflammatory-fibroblasts-and-myofibroblasts-in-pancreatic-cancer
#19
Daniel Öhlund, Abram Handly-Santana, Giulia Biffi, Ela Elyada, Ana S Almeida, Mariano Ponz-Sarvise, Vincenzo Corbo, Tobiloba E Oni, Stephen A Hearn, Eun Jung Lee, Iok In Christine Chio, Chang-Il Hwang, Hervé Tiriac, Lindsey A Baker, Dannielle D Engle, Christine Feig, Anne Kultti, Mikala Egeblad, Douglas T Fearon, James M Crawford, Hans Clevers, Youngkyu Park, David A Tuveson
Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28232469/a-myeloid-tumor-suppressor-role-for-nol3
#20
Robert F Stanley, Richard T Piszczatowski, Boris Bartholdy, Kelly Mitchell, Wendy M McKimpson, Swathi Narayanagari, Dagmar Walter, Tihomira I Todorova, Cassandra Hirsch, Hideki Makishima, Britta Will, Christine McMahon, Kira Gritsman, Jaroslaw P Maciejewski, Richard N Kitsis, Ulrich Steidl
Despite the identification of several oncogenic driver mutations leading to constitutive JAK-STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3(-/-) MPN mice harbor an expanded Thy1(+)LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias...
March 6, 2017: Journal of Experimental Medicine
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