title: Irgm1 promotes M1 but not M2 macrophage polarization in atherosclerosis pathogenesis and development.
abstract: 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.
  
  
  
  We used apolipoprotein E (ApoE) knockout and Irgm1 haplodeficient mice and induced atherosclerosis with high-cholesterol diet for the indicated months. Atherosclerotic arteries were collected from patients undergoing vascular surgery, to determine the lesional expression of Irgm1 and distribution of M1/M2 populations.
  
  
  
  Our results showed that IRGM/Irgm1 expression was increased in atherosclerotic artery samples (1.7-fold, p=0.0045) compared with non-atherosclerotic arteries, which was consistent with findings in the murine experimental atherosclerosis model (1.9-fold, p=0.0002). IRGM/Irgm1 expression was mostly found in lesional M1 macrophages. Haplodeficiency of Irgm1 in ApoE(-/-) mice resulted in reduced infiltrating M1 macrophages in atheroma (94%, p=0.0002) and delayed development of atherosclerotic plaques. In vitro experiments also confirmed that Irgm1 haplodeficiency reduced iNOS expression of polarized M1 macrophages (81%, p=0.0034), with negligible impact on the M2 phenotype. Moreover, we found that Irgm1 haplodeficiency in mice significantly reduced expression level of M1 function-related transcription factors, interferon regulatory factor (Irf) 5 and Irf8, but not Irf4, an M2-related transcription factor.
  
  
  
  This study shows that Irgm1/IRGM participates in the polarization of M1 macrophage and promotes development of atheroma in murine experimental atherosclerosis.
authors.affiliation: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
authors.forename: Jiangtian
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China.
authors.forename: Zhaoying
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China.
authors.forename: Zhongze
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China.
authors.forename: Ruikai
authors.initials: R
authors.lastname: Chai
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China.
authors.forename: Tongshuai
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Immunology, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, Harbin, 150081, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Pei
authors.affiliation: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Immunology, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, Harbin, 150081, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China; Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China. Electronic address: lihulun@hrbmu.edu.cn.
authors.forename: Hulun
authors.initials: H
authors.lastname: Li
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China; Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, Harbin, 150081, China. Electronic address: sunbo@hrbmu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D050197:Atherosclerosis / Q000097:blood* / Q000235:genetics*; D016764:Cell Polarity; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D002784:Cholesterol; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; C096000:Ifi1 protein, mouse; C494258:Irf1 protein, mouse; C513539:IRGM protein, human
keywords: Atherosclerosis; IRGM/Irgm1; Macrophage; Polarization