P38α deficiency in macrophages ameliorates murine experimental colitis by regulating inflammation and immune process

Abstract

IntroductionP38α is a mitogen-activated protein kinase (MAPK) that mediates inflammatory responses. P38α alterations have been associated with the inflammation-related diseases. However, the role of macrophages-derived p38α in dextran sulfate sodium (DSS)-induced murine experimental colitis remains unclear. ObjectivesWe characterized the role of macrophages-derived p38α in DSS-induced colitis. MethodsThe expression of macrophage-derived p38α in human colitis and normal tissues was measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. Macrophage-specific p38α knockout (p38αΔMφ) and wild type (WT) mice administrated by 3% DSS were used to establish experimental colitis. The alterations in inflammatory cytokines, intestinal epithelial barrier, cell proliferation and cell apoptosis between p38αΔMφ and WT groups were determined by IHC, immunofluorescence (IF), TdT-mediated dUTP Nick-End Labeling (TUNEL) and Western blot analyses. The enriched pathways between p38αΔMφ and WT groups were identified by RNA-seq and KEGG analysis. SB203580 and BIRB796 as the p38 MAPK inhibitors were used to treat DSS-induced colitis. Resultsp38α was co-localized with CD68 in the cytoplasm and their co-expression indicated an increased level in colitis tissues as compared with the normal tissues. P38α deficiency in macrophages was sufficient to suppress the exacerbated clinical symptoms and inflammation responses in experimental colitis, followed by reducing cytokine release, increasing MUC-2 and Claudin-2 secretion and promoting colonic mucosa repair. Further investigations validated that the immune process-related factors such as Lgals9, Rtp4, Ddx60, Nlrp1b, Hsh2d, Oas2 and Oas3 were upregulated in colon tissues from p38αΔMφ group as compared with the WT group. Inhibition of p38 MAPK attenuated DSS-induced colitis. ConclusionOur findings demonstrated that p38α deficiency in macrophages ameliorated murine experimental colitis by regulating inflammation and immune process.