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Qun Huang, Bin Chen, Yafei Li, Xihong Li
To investigate the role of immune-related GTPase M1 (IRGM1) in cortical neurons autophagy in mice with sepsis induced brain injury (SIBI).
 Methods: Sixty wild-type C57BL/6 mice and sixty IRGM1 gene knockout C57BL/6 mice were randomly divided into 4 groups: a sham-operated wild-type (SWT) group, a cecal ligation and puncture (CLP) model wild-type (MWT) group, a sham-operated knockout (SKO) group, and a CLP model knockout (MKO) group. Models of mice with sepsis were established by CLP. Six hours of after CLP, the neurobehavioral scores for mice were recorded...
December 28, 2017: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
Swati Roy, Amin Esmaeilniakooshkghazi, Srinivas Patnaik, Yaohong Wang, Sudeep P George, Afzal Ahrorov, Jason K Hou, Allan J Herron, Hiromi Sesaki, Seema Khurana
BACKGROUND & AIMS: Cell stress signaling pathways result in phosphorylation of the eukaryotic translation initiation factor 2 subunit alpha (EIF2S1 or EIF2A), which affects regulation of protein translation. Translation reprogramming mitigates stress by activating pathways that result in autophagy and cell death, to eliminate damaged cells. Actin is modified during stress and EIF2A is dephosphorylated to restore homeostasis. It is not clear how actin affects EIF2A signaling. We studied the actin-binding proteins villin 1 (VIL1) and gelsolin (GSN) in intestinal epithelial cells (IECs) to determine whether they respond to cell stress response and affect signaling pathways...
December 21, 2017: Gastroenterology
Kathleen M Azzam, Jennifer H Madenspacher, Derek W Cain, Lihua Lai, Kymberly M Gowdy, Prashant Rai, Kyathanahalli Janardhan, Natasha Clayton, Willie Cunningham, Heather Jensen, Preeyam S Patel, John F Kearney, Gregory A Taylor, Michael B Fessler
The pathogenesis of primary Sjogren's syndrome (SS), an autoimmune disease that targets the mucosa of exocrine tissues, is poorly understood. Although several mouse models have been developed that display features of SS, most of these are within the larger context of a lupus-like presentation. Immunity-related GTPase family M protein 1 (Irgm1) is an interferon-inducible cytoplasmic GTPase that is reported to regulate autophagy and mitochondrial homeostasis. Here, we report that naive Irgm1-/- mice display lymphocytic infiltration of multiple mucosal tissues including the lung in a manner reminiscent of SS, together with IgA class-predominant autoantibodies including anti-Ro and anti-La...
August 17, 2017: JCI Insight
Sudha B Singh, Henry C Lin
Impaired Paneth cell expression of antimicrobial protein (AMP) lysozyme is found in patients with Crohn's disease with the autophagy gene ATG16L1 risk allele, in mice with mutations in autophagy genes Atg16L1, Atg5 and Atg7, and in Irgm1 knockout mice. Defective autophagy is also associated with expansion of resident Gram-negative bacteria in the intestinal lumen. These findings suggest that autophagy may control extracellular resident microbes by governing expression of lysozyme. To test the hypothesis that autophagy may have a defensive role in host response to resident extracellular microbes, we investigated the relationship between gut microbes, autophagy, and lysozyme...
August 2017: Innate Immunity
Yanyan Bao, Yingjie Gao, Yujing Shi, Xiaolan Cui
H1N1, a major pathogenic subtype of influenza A virus, causes a respiratory infection in humans and livestock that can range from a mild infection to more severe pneumonia associated with acute respiratory distress syndrome. Understanding the dynamic changes in the genome and the related functional changes induced by H1N1 influenza virus infection is essential to elucidating the pathogenesis of this virus and thereby determining strategies to prevent future outbreaks. In this study, we filtered the significantly expressed genes in mouse pneumonia using mRNA microarray analysis...
June 2017: Virus Genes
Elyse A Schmidt, Brian E Fee, Stanley C Henry, Amanda G Nichols, Mari L Shinohara, Jeffrey C Rathmell, Nancie J MacIver, Jörn Coers, Olga R Ilkayeva, Timothy R Koves, Gregory A Taylor
The immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear...
March 17, 2017: Journal of Biological Chemistry
Yanwen Xu, Zhongze He, Zhaoying Li, Shaohong Fang, Yun Zhang, Cong Wan, Yiming Ma, Peng Lin, Chuanliang Liu, Guangyou Wang, Rui Li, Jiwei Zhu, Ying Li, Lili Mu, Yao Zhang, Jinghua Wang, Qingfei Kong, Hulun Li, Bo Sun
The classically activated (M1) macrophage has been shown to play an indispensable role in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). However, most studies focus on the effect of macrophage on CNS demyelination of EAE; whether the M1 macrophage participates in early EAE and the molecular mechanism underlying remains unclear. Here, we showed that the immunity-related GTPase family member 1 (Irgm1), also known as LRG-47, was expressed in M1 macrophages of draining lymph nodes (dLNs) from C57BL/6 mice with early EAE, and the IRGM1 heterozygote substantially reduced M1 macrophage accumulation in dLNs and spleen of the primary EAE stage...
February 2017: Journal of Leukocyte Biology
Shaohong Fang, Yanwen Xu, Yun Zhang, Jiangtian Tian, Ji Li, Zhaoying Li, Zhongze He, Ruikai Chai, Fang Liu, Tongshuai Zhang, Shuang Yang, Chunying Pei, Xinxin Liu, Peng Lin, Hongwei Xu, Bo Yu, Hulun Li, Bo Sun
BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory vascular disease related to macrophages uptake of low-density lipoprotein and their subsequent transformation into foam cells. M1 (inflammatory)/M2 (anti-inflammatory) balance was suggested to impact disease progression. In this study, we investigated whether the immunity related GTPase (Irgm1) regulates macrophage polarization during atherosclerosis development. METHODS: We used apolipoprotein E (ApoE) knockout and Irgm1 haplodeficient mice and induced atherosclerosis with high-cholesterol diet for the indicated months...
August 2016: Atherosclerosis
Jelena Maric-Biresev, Julia P Hunn, Oleg Krut, J Bernd Helms, Sascha Martens, Jonathan C Howard
BACKGROUND: The interferon-γ (IFN-γ)-inducible immunity-related GTPase (IRG), Irgm1, plays an essential role in restraining activation of the IRG pathogen resistance system. However, the loss of Irgm1 in mice also causes a dramatic but unexplained susceptibility phenotype upon infection with a variety of pathogens, including many not normally controlled by the IRG system. This phenotype is associated with lymphopenia, hemopoietic collapse, and death of the mouse. RESULTS: We show that the three regulatory IRG proteins (GMS sub-family), including Irgm1, each of which localizes to distinct sets of endocellular membranes, play an important role during the cellular response to IFN-γ, each protecting specific membranes from off-target activation of effector IRG proteins (GKS sub-family)...
April 20, 2016: BMC Biology
Yanan Gao, Jingjiao Wu, Meijuan Zhang, Min Hou, Minjun Ji
Interferon-inducible GTPase LRG-47 (also named immune-related GTPase M, Irgm1) is a member of the p47 GTPase family that has been shown to regulate host resistance to intracellular pathogens. Little knowledge has been known about the role of LRG-47 in host's responses to extracellular pathogens. To investigate possible roles of LRG-47 in the course of Schistosoma japonicum infection, LRG-47-deficient (LRG-47(-/-)) and wild-type (WT) mice were challenged with cercariae of S. japonicum, and the cellular and humoral responses in mice were analyzed...
March 2016: Parasitology Research
Youngae Lee, Miwa Sasai, Ji Su Ma, Naoya Sakaguchi, Jun Ohshima, Hironori Bando, Tatsuya Saitoh, Shizuo Akira, Masahiro Yamamoto
Also known as Sqstm1, p62 is a selective autophagy adaptor with a ubiquitin-binding domain. However, the role of p62 in the host defense against Toxoplasma gondii infection is unclear. Here, we show that interferon γ (IFN-γ) stimulates ubiquitin and p62 recruitment to T. gondii parasitophorous vacuoles (PVs). Some essential autophagy-related proteins, but not all, are required for this recruitment. Regardless of normal IFN-γ-induced T. gondii clearance activity and ubiquitination, p62 deficiency in antigen-presenting cells (APCs) and mice diminishes the robust IFN-γ-primed activation of CD8(+) T cells that recognize the T...
October 13, 2015: Cell Reports
Nadia Kavrochorianou, Maria Evangelidou, Melina Markogiannaki, Michael Tovey, George Thyphronitis, Sylva Haralambous
Although interferon-β is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2-ifnar1 transgene on a interferon-α/β receptor 1 null genetic background, thus allowing expression of the interferon-α/β receptor 1 and hence, a functional type I interferon receptor exclusively on T cells...
January 2016: Journal of Leukocyte Biology
Henry W Murray, Marisa Mitchell-Flack, Gregory A Taylor, Xiaojing Ma
In C57BL/6 mice, Leishmania donovani infection in the liver provoked IFN-γ-induced expression of the immunity-related GTPases (IRG), Irgm1 and Irgm3. To gauge the antileishmanial effects of these macrophage factors in the liver, intracellular infection was analyzed in IRG-deficient mice. In early- (but not late-) stage infection, Irgm3(-/-) mice failed to properly control parasite replication, generated little tissue inflammation and were hyporesponsive to pentavalent antimony (Sb) chemotherapy. Observations limited to early-stage infection in Irgm1(-/-) mice demonstrated increased susceptibility and virtually no inflammatory cell recruitment to heavily-parasitized parenchymal foci but an intact response to chemotherapy...
October 2015: Experimental Parasitology
Linlu Tian, Lixian Li, Wenjing Xing, Rui Li, Chunying Pei, Xiao Dong, Yanran Fu, Changcong Gu, Xize Guo, Yulong Jia, Guangyou Wang, Jinghua Wang, Bo Li, Huan Ren, Hongwei Xu
Melanoma is one of the most aggressive skin cancers and is well known for its high metastatic rate. Studies have shown that epithelial mesenchymal transition (EMT) is essential for melanoma cell metastasis. However, the molecular mechanisms underlying EMT are still not fully understood. We have shown that IRGM1, a member of immunity-related GTPase family that regulates immune cell motility, is highly expressed by melanoma cells. The current study aimed to explore whether and how IRGM1 may regulate melanoma cell metastasis...
2015: Scientific Reports
Jintao Guo, James A McQuillan, Belinda Yau, Gregory S Tullo, Carole A Long, Patrick Bertolino, Ben Roediger, Wolfgang Weninger, Gregory A Taylor, Nicholas H Hunt, Helen J Ball, Andrew J Mitchell
Gamma interferon (IFN-γ) drives antiparasite responses and immunopathology during infection with Plasmodium species. Immunity-related GTPases (IRGs) are a class of IFN-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used the Plasmodium berghei ANKA (PbA) model in which mice develop experimental cerebral malaria (ECM) to study the roles of IRGM1 and IRGM3 in immunopathology...
April 2015: Infection and Immunity
Motamed Elsayed Mahmoud, Fumiki Ui, Doaa Salman, Maki Nishimura, Yoshifumi Nishikawa
The apical complex of Toxoplasma gondii enables it to invade virtually all nucleated cells in warm-blooded animals, including humans, making it a parasite of global importance. Anti-T. gondii cellular defence mechanisms depend largely on interferon (IFN)-γ production by immune cells. However, the molecular mechanism of IFN-β-mediated defence remains largely unclear. Here, mouse peritoneal macrophages and murine embryonic fibroblasts (MEFs) primed with recombinant IFN-β and IFN-γ showed different pathways of activation...
July 2015: Cellular Microbiology
H Dong, L Tian, R Li, C Pei, Y Fu, X Dong, F Xia, C Wang, W Li, X Guo, C Gu, B Li, A Liu, H Ren, C Wang, H Xu
Interferon gamma (IFNg) has been known as the regulator for both tumor immune surveillance and tumorgenesis. However, mechanisms underlying the resistance of tumor cell to IFNg have yet been fully understood. In the current study, we showed that immunity-related GTPase family member 1 (mouse: Irgm1; human: IRGM) is essential for IFNg-mediated regulation of tumor cell growth in melanoma. IRGM/Irgm1 was highly expressed in human and mouse melanoma. IFNg and starvation synergistically induced Irgm1 expression in melanoma B16 cells...
October 16, 2015: Oncogene
Lulu Sun, Hiroyuki Miyoshi, Sofia Origanti, Timothy J Nice, Alexandra C Barger, Nicholas A Manieri, Leslie A Fogel, Anthony R French, David Piwnica-Worms, Helen Piwnica-Worms, Herbert W Virgin, Deborah J Lenschow, Thaddeus S Stappenbeck
The host immune system functions constantly to maintain chronic commensal and pathogenic organisms in check. The consequences of these immune responses on host physiology are as yet unexplored, and may have long-term implications in health and disease. We show that chronic viral infection increases epithelial turnover in multiple tissues, and the antiviral cytokines type I interferons (IFNs) mediate this response. Using a murine model with persistently elevated type I IFNs in the absence of exogenous viral infection, the Irgm1(-/-) mouse, we demonstrate that type I IFNs act through nonepithelial cells, including macrophages, to promote increased epithelial turnover and wound repair...
January 14, 2015: Cell Host & Microbe
Stanley C Henry, Elyse A Schmidt, Michael B Fessler, Gregory A Taylor
The Immunity-Related GTPases (IRG) are a family of large GTPases that mediate innate immune responses. Irgm1 is particularly critical for immunity to bacteria and protozoa, and for inflammatory homeostasis in the intestine. Although precise functions for Irgm1 have not been identified, prior studies have suggested roles in autophagy/mitophagy, phagosome remodeling, cell motility, and regulating the activity of other IRG proteins. These functions ostensibly hinge on the ability of Irgm1 to localize to intracellular membranes, such as those of the Golgi apparatus and mitochondria...
2014: PloS One
Rajkumar Cheluvappa, Annie S Luo, Michael C Grimm
BACKGROUND: When done at a young age, appendicitis followed by appendectomy (AA) offers protection against ulcerative colitis development in later life. We developed the first ever murine AA model. Using this model, we showed earlier that previous AA ameliorated colitis. We aimed to determine whether autophagy genes contribute to the anti-colitis protection conferred by AA, and if so, to delineate the autophagy-linked genes involved in this. METHODS: Mice with 2 laparotomies each served as controls (sham-sham)...
May 2014: Inflammatory Bowel Diseases
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