CD73 Promotes Intestinal Inflammatory Responses By Regulating Macrophages Differentiation In Ulcerative Colitis

Objective: To investigate the mechanism by which CD73 acts on macrophages to influence the inflammatory response in UC,we compared the levels and changes of CD73 in UC patients and healthy people by detecting the levels of CD73 in intestinal tissues.We further explored the changes and mechanisms of macrophages in the intestinal immune inflammatory response to understand the pathogenesis of CD73 action on macrophages in UC.Therefore,providing a potential therapeutic target of CD73 in UC.Methods: In this study,we examined CD73 expression in the inflamed mucosa of patients with UC using q RT-PCR,western blot and IHC.APCP has been used to block the expression of CD73.Furthermore,we measured the m RNA levels of proinflammatory mediators related with macrophages in blocking of CD73 were examined by q RT-PCR.Moreover,we determined the regulatory function of CD73 in intestinal inflammation by administering APCP in a mouse model of DSS-induced colitis.Finally,the potential signal pathway of CD73 in inflammatory immunity was explored by Western blotting.Results: Notably,we found that CD73 expression was significantly increased in the colonic mucosal tissues of patients with UC.Besides,blockade of CD73 suppressed the expression of proinflammatory cytokines and promoted that of anti-inflammatory cytokines in mouse macrophages.Furthermore,we investigated that CD73 enhanced M2 macrophage polarization.Moreover,CD73 blockade markedly alleviated DSS-induced colitis in mice,as characterized by reduced weight loss,diarrhea reduction and bloody stool.Mechanistically,we showed that CD73 regulated macrophage differentiation via NF-κB and ERK signaling pathways.Conclusion: In conclusion,CD73 modulates intestinal macrophage polarization via the NF-κB and ERK signaling pathway and maintains intestinal homoeostasis.CD73 blockaded macrophages downregulated pro-inflammatory cytokines(e g,IL-10,TNF-α,IL-6)which further aggravate intestinal inflammation.In addition,blockade of CD73 contributes to the increase of M2-like macrophage polarization and the decrease of M1-like macrophage polarization.Our study highlights that CD73 acts as a critical role in regulating macrophage type and maintaining intestinal mucosal homoeostasis through the NF-κB and ERK axis.