Goblet cell loss, which leads to the reduction of mucin secretion, is a hallmark of ulcerative colitis (UC). We previously reported that steroid receptor coactivator 3 (SRC-3), a transcriptional coactivator, contributes to host defense against Citrobacter rodentium by recruiting neutrophils, suggesting a role of SRC-3 in intestine homeostasis. However, the biological role of SRC-3 in UC remains unclear. Here, we showed that SRC-3-/- mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis compared with wild-type mice after oral administration of 2% DSS dissolved in drinking water. After oral administration of 2% DSS, SRC-3-/- mice displayed higher mortality rate, significant body weight loss, and higher clinical symptom scores compared to wild-type mice. SRC-3-/- mice suffered a severe loss of mature colonic goblet cells, leading to more severe histopathology and more proinflammatory cytokine production. Mechanistically, SRC-3-/- mice exhibited a decreased expression of transcription factor KLF4 in the colons, which is responsible for colonic goblet cell differentiation and maturation. At the molecular level, SRC-3 cooperated with c-Fos to promote KLF4 expression at the transcriptional level. These results demonstrate that SRC-3 can ameliorate DSS-induced colitis by inhibiting inflammation and promoting colonic goblet cell differentiation and maturation through enhancing the expression of transcriptional factor KLF4, which is responsible for colonic goblet cell differentiation and maturation.
Steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator that interacts with nuclear receptors and some other transcription factors to enhance their effects on target gene transcription. We previously reported that SRC-3-deficient (SRC-3−/−) mice are super susceptible to E. coil-induced septic peritonitis due to uncontrolled inflammation and a defect in bacterial clearance. In this study, we observed significant upregulation of SRC-3 in the colonic epithelial cells in response to Citrobacter rodentium infection. Based on these findings, we hypothesized that SRC-3 is involved in host defense against attaching and effacing (A/E) bacterial infection. We compared the responses of SRC-3−/− and wild-type mice to intestinal C. rodentium infection. We found that SRC-3−/− mice exhibited delayed clearance of C. rodentium and more severe tissue pathology after oral infection with C. rodentium compared with wild-type mice. SRC-3−/− mice expressed normal antimicrobial peptides in the colons, but exhibited delayed recruitment of neutrophils into the colonic mucosa. Accordingly, SRC-3−/− mice showed a delayed induction of CXCL2 and CXCL5 in the colonic epithelial cells, which are responsible for neutrophil recruitment. At the molecular level, we found that SRC-3 can activate the NF-κB signaling pathway to promote CXCL2 expression at the transcriptional level. Collectively, we show that SRC-3 contributes to host defense against enteric bacteria at least in part via upregulating CXCL2 expression to recruit neutrophils.
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