title: Irgm1 is required for the inflammatory function of M1 macrophage in early experimental autoimmune encephalomyelitis.
abstract: 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. In vitro silence of IRGM1 in M1 macrophages impaired NOS2 expression and inflammatory cytokine release. We also found that IRGM1 knockout (Irgm1-/-) in M1 macrophages increased Akt activation but attenuated NF-κB p65 activation, which may reveal Irgm1-mediated mechanisms of action. Interestingly, macrophage depletion in vivo inhibited Th1/Th17 differentiation in the spleen and promoted regulatory T cell (Treg) polarization in dLNs at 7 d postimmunization (dpi). Moreover, we observed that M1 macrophages in vitro promoted Th1/Th17 differentiation, which was reversed by treatment with IRGM1 small interfering RNA (siRNA), anti-TNF-α, or anti-IL-1β mAb. These results suggest that the M1 macrophage may promote Th1/Th17 cell differentiation during the early EAE, and the proinflammatory function of M1 cells requires Irgm1.
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Zhongze
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Zhaoying
authors.initials: Z
authors.lastname: Li
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China.|Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wan
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Chuanliang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Guangyou
authors.initials: G
authors.lastname: Wang
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Forensic Medicine, Basic Medical Science College, Harbin Medical University, Harbin, China; and.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Tumor Department No. 2, 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Mu
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Kong
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China; lihulun@hrbmu.edu.cn.|The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China.
authors.forename: Hulun
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Education Department of Heilongjiang Province, Harbin Medical University, Harbin, China; sunbo@hrbmu.edu.cn.|The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D004002:Clodronic Acid / Q000494:pharmacology; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020868:Gene Silencing / Q000187:drug effects; D006579:Heterozygote; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D008081:Liposomes; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C096000:Ifi1 protein, mouse; D008081:Liposomes; D016328:NF-kappa B; D004002:Clodronic Acid; D051057:Proto-Oncogene Proteins c-akt; D019204:GTP-Binding Proteins
keywords: Akt; NF-κB; Th cell; differentiation