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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...
July 21, 2016: 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)...
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
Caterina Strisciuglio, Renata Auricchio, Massimo Martinelli, Annamaria Staiano, Francesca Paola Giugliano, Marialuisa Andreozzi, Marina De Rosa, Eleonora Giannetti, Carmela Gianfrani, Paola Izzo, Riccardo Troncone, Erasmo Miele
BACKGROUND AND AIMS: Little evidence demonstrating the correlation between several single nucleotide polymorphisms and a specific phenotype of Crohn's disease has been reported in children. We investigated the relationship between autophagy genes variants and clinical features in our children with Crohn's disease. METHODS: Genotyping for ATG16L1, NOD2/CARD15, and IRGM1 was performed in 80 consecutive patients with Crohn's disease (median age: 11 years; range: 0...
June 2014: Digestive and Liver Disease
Bo Liu, Ajay S Gulati, Viviana Cantillana, Stanley C Henry, Elyse A Schmidt, Xiaoju Daniell, Emily Grossniklaus, Alexi A Schoenborn, R Balfour Sartor, Gregory A Taylor
Crohn's disease (CD) is a chronic, immune-mediated, inflammatory disorder of the intestine that has been linked to numerous susceptibility genes, including the immunity-related GTPase (IRG) M (IRGM). IRGs comprise a family of proteins known to confer resistance to intracellular infections through various mechanisms, including regulation of phagosome processing, cell motility, and autophagy. However, despite its association with CD, the role of IRGM and other IRGs in regulating intestinal inflammation is unclear...
October 15, 2013: American Journal of Physiology. Gastrointestinal and Liver Physiology
Helen M Springer, Michael Schramm, Gregory A Taylor, Jonathan C Howard
The IFN-inducible protein Irgm1 (LRG-47) belongs to the family of immunity-related GTPases that function in cell-autonomous resistance against intracellular pathogens in mice. Irgm1 deficiency is associated with a severe immunodeficiency syndrome. The protein has been variously interpreted as a direct effector molecule on bacterial phagosomes or on other organelles or as an inducer of autophagy. In this study, we re-examined one of these claims, namely that Irgm1 targets mycobacterial and listerial phagosomes...
August 15, 2013: Journal of Immunology: Official Journal of the American Association of Immunologists
Arun K Haldar, Hector A Saka, Anthony S Piro, Joe Dan Dunn, Stanley C Henry, Gregory A Taylor, Eva M Frickel, Raphael H Valdivia, Jörn Coers
Interferon-inducible GTPases of the Immunity Related GTPase (IRG) and Guanylate Binding Protein (GBP) families provide resistance to intracellular pathogenic microbes. IRGs and GBPs stably associate with pathogen-containing vacuoles (PVs) and elicit immune pathways directed at the targeted vacuoles. Targeting of Interferon-inducible GTPases to PVs requires the formation of higher-order protein oligomers, a process negatively regulated by a subclass of IRG proteins called IRGMs. We found that the paralogous IRGM proteins Irgm1 and Irgm3 fail to robustly associate with "non-self" PVs containing either the bacterial pathogen Chlamydia trachomatis or the protozoan pathogen Toxoplasma gondii...
2013: PLoS Pathogens
Fucan Xia, Rui Li, Chaodong Wang, Shuang Yang, Linlu Tian, Haiyan Dong, Chunying Pei, Shuyu He, Pengyu Jiang, Hairong Cheng, Shaohong Fang, Hulun Li, Hongwei Xu
Macrophage derived foam cells are actively involved in the initial phase of atherosclerosis. Uptake of modified lipoprotein such as oxidized LDL (oxLDL) is a critical step for foam cell formation. CD36 is the major receptor mediating oxLDL uptake by macrophage. However, the molecular mechanism underlying CD36 mediated oxLDL uptake remains unclear. Here we reported that IRGM1 (IRGM in human), a member of immunity-related small GTPase family, is essential for the actin-dependent CD36 mediated oxLDL uptake by macrophage...
2013: Scientific Reports
Anna D Tischler, Rachel L Leistikow, Meghan A Kirksey, Martin I Voskuil, John D McKinney
Mycobacterium tuberculosis persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-γ). We identified the M. tuberculosis phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-γ-dependent immunity. A ΔpstA1 mutant was fully virulent in IFN-γ(-/-) mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-γ-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox)...
January 2013: Infection and Immunity
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