MARCH1 E3 Ubiquitin Ligase Dampens the Innate Inflammatory Response by Modulating Monocyte Functions in Mice

• Published in: The Journal of immunology (1950) Vol. 198; no. 2; pp. 852 - 861
• Main Authors: Galbas, Tristan, Raymond, Maxime, Sabourin, Antoine, Bourgeois-Daigneault, Marie-Claude, Guimont-Desrochers, Fanny, Yun, Tae Jin, Cailhier, Jean-François, Ishido, Satoshi, Lesage, Sylvie, Cheong, Cheolho, Thibodeau, Jacques
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 15-01-2017
• Subjects: Adaptive immunity; Animals; Arteriosclerosis; Asthma; Bacteria; Bone marrow; Cell activation; Chimeras; Cytokines; Disease Models, Animal; Egress; Endotoxemia; Endotoxemia - immunology; Endotoxins; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Histocompatibility Antigens Class II - immunology; Homing; Immune response; Immunity, Innate - immunology; Inflammation - immunology; Inflammatory diseases; Inflammatory response; Innate immunity; Interleukin 10; Lethal dose; Leukocytes (neutrophilic); Leukocytes (polymorphonuclear); Lipopolysaccharides; Lipopolysaccharides - immunology; Lymphocyte Activation - immunology; Major histocompatibility complex; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Monocytes - immunology; Natural killer cells; Organs; Pathogenesis; Proteasomes; Real-Time Polymerase Chain Reaction; Rodents; Shock; Signal transduction; Spleen; TLR4 protein; Toll-like receptors; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - immunology; Ubiquitination
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601168

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 Ly6C
to 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.