The E3 Ligase FBXW7 Increased The Severity Of Colitis By Augment Recruitment Of CX3CR1^int Proinflammatory Macrophages

Inflammatory bowel disease (IBD) is a chronic and recurrent intestinal inflammatory diseases that is mediated by immunology, such as Crohn’s disease and ulcerative colitis. The precise aetiology of IBD remains unclear, but several factors that make a major contribution to disease pathogenesis have been identified, these fall into three distinct categories:genetic factors, the host immune system, and environmental factors such as the gut microbiota, which is dominated by intestinal bacteria. Protein ubiquitination is important to the immune system in aspect of signal transduction and then pathogen clearance. As a member of E3-ubiquitin-ligase, FBXW7 is reported to modulate multiple biological processes such as tumor growth, lipid metabolism, cell proliferation/differentiation, or the homeostasis of stem cells. However, the role of FBXW7 in inflammatory immunity is poorly clarified.In our study, we observed that mice with myeloid-specific deficiency of FBXW7 (Lysm-Cre+FBXW7f/f) are more susceptible to intestinal inflammation induced by DSS (Dextran sulfate sodium salt) and TNBS (Picrylsulfonic acid solution) and recover from injuries faster compared to WT littermates. In Intestinal tissue and lamina propria cells of WT mice expression higher levels of IL-6 and TNF-a.and lower IL-10. WT macrophages and bone marrow derived macrophage (BMDM) showed increased levels of IL-6 and TNF-a, decreased levels of IL-10 after stimulated with LPS in vitro.Macrophage always play an important role in inflammation, Ly6C+ mononuclear cells of mice intestinal lamina propria can differentiate into the proinflammatory CX3CR1int macrophages, In the case of acute inflammation, these macrophages have an effect on infection and inflammation, aggravating the happening of the disease. so we found that the deficiency of FBXW7 dampened the recruitment of CX3CR1int proinflammatory macrophages in intestinal inflammation mice. Moreover, deficiency of FBXW7 reduced the capacity of macrophages to produce chemotactic factors CCL2 and CCL7, which can recruit proinflammatory macrophages to local inflammation and involved in the inflammatory response.This study reveals that FBXW7 plays an important role in inflammatory bowel disease, uncovering a novel role of FBXW7 in regulating inflammation, other than many known biological processes such as tumor growth, lipid metabolism, cell proliferation, differentiation, or the homeostasis of stem cells. It may provide new ideas and visions to explain the occurrence and development of inflammatory bowel disease, puts forward new train of thought and basic theories for inflammatory bowel disease treatment.