title: MARCH1 E3 Ubiquitin Ligase Dampens the Innate Inflammatory Response by Modulating Monocyte Functions in Mice.
abstract: Ubiquitination was recently identified as a central process in the pathogenesis and development of numerous inflammatory diseases, such as obesity, atherosclerosis, and asthma. Treatment with proteasomal inhibitors led to severe side effects because ubiquitination is heavily involved in a plethora of cellular functions. Thus, new players regulating ubiquitination processes must be identified to improve therapies for inflammatory diseases. In addition to their role in adaptive immunity, endosomal MHC class II (MHCII) molecules were shown to modulate innate immune responses by fine tuning the TLR4 signaling pathway. However, the role of MHCII ubiquitination by membrane associated ring-CH-type finger 1 (MARCH1) E3 ubiquitin ligase in this process remains to be assessed. In this article, we demonstrate that MARCH1 is a key inhibitor of innate inflammation in response to bacterial endotoxins. The higher mortality of March1-/-mice challenged with a lethal dose of LPS was associated with significantly stronger systemic production of proinflammatory cytokines and splenic NK cell activation; however, we did not find evidence that MARCH1 modulates LPS or IL-10 signaling pathways. Instead, the mechanism by which MARCH1 protects against endotoxic shock rests on its capacity to promote the transition of monocytes from Ly6CHito Ly6C+/-Moreover, in competitive bone marrow chimeras, March1-/-monocytes and polymorphonuclear neutrophils outcompeted wild-type cells with regard to bone marrow egress and homing to peripheral organs. We conclude that MARCH1 exerts MHCII-independent effects that regulate the innate arm of immunity. Thus, MARCH1 might represent a potential new target for emerging therapies based on ubiquitination reactions in inflammatory diseases.
authors.affiliation: Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec H3T 1J4, Canada.|Laboratoire d'Immunologie Moléculaire, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
authors.forename: Tristan
authors.initials: T
authors.lastname: Galbas
authors.affiliation: Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec H3T 1J4, Canada.|Laboratoire d'Immunologie Moléculaire, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Raymond
authors.affiliation: Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec H3T 1J4, Canada.|Laboratoire d'Immunologie Moléculaire, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
authors.forename: Antoine
authors.initials: A
authors.lastname: Sabourin
authors.affiliation: Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec H3T 1J4, Canada.|Laboratoire d'Immunologie Moléculaire, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Bourgeois-Daigneault
authors.affiliation: Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec H3T 1J4, Canada.|Immunology-Oncology Section, Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada.
authors.forename: Fanny
authors.initials: F
authors.lastname: Guimont-Desrochers
authors.affiliation: Laboratoire de Physiologie Cellulaire et Immunologie, Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Yun
authors.affiliation: Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada; and.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cailhier
authors.affiliation: Department of Microbiology, Hyogo College of Medicine 1-1, Mukogawa-cho, Nishinomiya 663-8501, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.affiliation: Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec H3T 1J4, Canada.|Immunology-Oncology Section, Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada.
authors.forename: Sylvie
authors.identifier: 0000-0002-0968-2795
authors.initials: S
authors.lastname: Lesage
authors.affiliation: Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec H3T 1J4, Canada.|Laboratoire de Physiologie Cellulaire et Immunologie, Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.affiliation: Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec H3T 1J4, Canada; jacques.thibodeau@umontreal.ca.|Laboratoire d'Immunologie Moléculaire, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Thibodeau
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000276:immunology*; D054875:Ubiquitination
chemical_list: D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; C545340:MARCH1 protein, mouse; D044767:Ubiquitin-Protein Ligases