SRC-3 protects intestine from DSS-induced colitis by inhibiting inflammation and promoting goblet cell

Wenbo Chen1,2, Minghui Zhuo2, Xuqiang Lu2

  • 1Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China.

Insights

Steroid receptor coactivator 3 (SRC-3) deficiency worsens dextran sulfate sodium (DSS)-induced colitis in mice. SRC-3 promotes goblet cell differentiation and reduces inflammation by enhancing KLF4 expression, crucial for intestinal homeostasis.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Immunology

Background:

  • Goblet cell loss and reduced mucin secretion characterize ulcerative colitis (UC).
  • Steroid receptor coactivator 3 (SRC-3) plays a role in host defense and intestinal homeostasis.
  • The specific role of SRC-3 in UC pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the biological role of SRC-3 in dextran sulfate sodium (DSS)-induced colitis, a model for UC.
  • To elucidate the molecular mechanisms by which SRC-3 influences intestinal inflammation and goblet cell function.

Main Methods:

  • Utilized SRC-3 knockout (SRC-3-/-) and wild-type mice in a DSS-induced colitis model.
  • Administered 2% DSS in drinking water to induce colitis.
  • Assessed mortality, body weight loss, clinical scores, colonic histopathology, goblet cell counts, and proinflammatory cytokine levels.
  • Analyzed the expression of transcription factor KLF4 and its regulation by SRC-3 and c-Fos.

Main Results:

  • SRC-3-/- mice exhibited increased susceptibility to DSS-induced colitis, with higher mortality, weight loss, and clinical scores.
  • These mice showed severe loss of colonic goblet cells, exacerbated histopathology, and elevated proinflammatory cytokine production.
  • SRC-3-/- mice displayed decreased colonic expression of KLF4, a key regulator of goblet cell differentiation.
  • SRC-3 was found to cooperate with c-Fos to transcriptionally enhance KLF4 expression.

Conclusions:

  • SRC-3 ameliorates DSS-induced colitis by inhibiting inflammation and promoting goblet cell differentiation and maturation.
  • This protective effect is mediated through SRC-3's enhancement of KLF4 expression, crucial for maintaining intestinal barrier function.
  • SRC-3 is a critical factor in intestinal homeostasis and warrants further investigation for UC therapeutic strategies.

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