The role of CMPK2 on IBD development by regulating macrophage polarization

Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. The polarization of macrophages to the M1 or M2 phenotype has a pivotal role in inflammation and host defense; however, the underlying molecular mechanism remains unclear. Cytidine/uridine monophosphate kinase 2 (CMPK2) is a nucleoside monophosphate kinase and is implicated in the synthesis of mitochondrial DNA (mtDNA). Here, we uncover a function of CMPK2 in promoting the pathogenesis of IBD. Using bioinformatics analysis, we identified CMPK2 involved with macrophage polarization. To address this issue, BMDMs were isolated from CMPK2^+/+ and CMPK2^-/- mice and then stimulated with lipopolysaccharide (LPS)/interferon γ (IFN-γ) or interleukin-4 (IL-4). CMPK2 deficiency in macrophages drastically abrogated M1 macrophage activation, while promoting M2 macrophage polarization. In addition, CMPK2 is involved in STAT1 activation in response to LPS/ IFN-γ stimulation. Further investigation revealed that CMPK2 binds to pyruvate kinase M2 (PKM2), which is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Taken together, our findings show that CMPK2 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.