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CD26 deficiency modulates macrophage polarization via targeting of STAT proteins in a mouse model of ulcerative colitis

Inflammatory bowel disease represents a chronic inflammation of the gastrointestinal tract and includes ulcerative colitis (UC), a disease characterized by the destruction of intestinal mucosa followed by an excessive and dysregulated activation of the immune system. In recent years, macrophages have been identified as essential elements that not only maintain intestinal homeostasis but also control the inflammatory response and mucosal healing. Macrophage polarization into either classically activated proinflammatory (M1) or alternatively activated anti-inflammatory (M2) subclass occurs as a response to the downstream signal of different cytokines so the regulation of M1/M2 balance has recently been targeted as a potential therapeutic strategy for UC. The inhibition of CD26, a multifunctional glycoprotein that regulates the immune response via its dipeptidyl peptidase (DP) 4 enzyme activity, was proven to have beneficial effects in various autoimmune inflammatory diseases but the role of DP8 and DP9, proteins with DP4-like activity, are not characterized in detail. We aimed to investigate the impact of CD26 deficiency on the process of macrophage polarization as well as DP8/9 expression profiles in the dextran sulfate sodium (DSS)-induced model of UC. Our results revealed that mRNA expression of M2 markers arginase 1 and Fizz were increased, while the expression of M1 marker inducible NO synthase was downregulated in CD26−/− mice with acute UC. Decreased STAT1 mRNA, as well as upregulated pSTAT6 and pSTAT3, additionally support the demonstrated activation of M2 macrophages under CD26 deficiency. Furthermore, we concluded that CD26 deficiency is not a key factor for the noted upregulation of DP8 and DP9 expression in UC development and resolution. In conclusion, we demonstrated that CD26 deficiency regulates macrophage polarization toward the anti- inflammatory M2 phenotype, which is driven by STAT6/STAT3 signaling pathways. This process is additionally enhanced by the reduction of M1 differentiation via the suppression of proinflammatory STAT1. Further studies should be done to investigate the clinical potential of CD26 inhibitors in the treatment of UC.

CD26, IBD, macrophage polarization, DP8, DP9

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