International immunopharmacology · 2026
Targeting IRF5 enhances S100A9-mediated granulocytic MDSC accumulation and suppressive function: a novel therapeutic strategy for ulcerative colitis.
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Chen Yi-Mei, Xiao Qi-Wen, Shi Yong-Jie, Zeng Shao-Na, Jia Hong-Yun, Zheng Xun, Huang Si-Cong
Аннотация
BACKGROUND: Ulcerative colitis (UC) progression involves dysregulated immune interactions. Myeloid-derived suppressor cells (MDSCs) exhibit therapeutic potential in inflammatory bowel disease, yet the mechanisms underlying their differentiation remain unclear. This study investigates the regulation of granulocytic MDSCs (G-MDSCs) by interferon regulatory factor 5 (IRF5).
METHODS: Dextran sulfate sodium (DSS)-induced murine colitis models were employed to evaluate IRF5 function, incorporating cellular analyses from IRF5 knockout (KO) and wild-type mice. Clinical relevance was assessed using peripheral blood and intestinal specimens from UC patients.
RESULTS: IRF5 expression was elevated in G-MDSCs from colitic mice. IRF5 deficiency markedly increased G-MDSC frequency and immunosuppressive activity, while monocytic MDSCs (M-MDSCs) remained unaffected. Rescue experiments confirmed that IRF5 KO-derived G-MDSCs alleviated colitis severity. Mechanistically, ChIP-qPCR, luciferase reporter assays, and western blotting demonstrate that IRF5 represses S100A9 transcriptionally, thereby limiting G-MDSC accumulation. S100A9 is a Ca2+-binding protein that is critical for MDSC expansion. Clinically, UC patients demonstrated elevated IRF5 expression, which inversely correlated with circulating G-MDSC levels.
CONCLUSIONS: IRF5 acts as a transcriptional brake on G-MDSC development through S100A9 signaling, establishing the IRF5/G-MDSC axis as a novel pharmacological target for UC therapy.
METHODS: Dextran sulfate sodium (DSS)-induced murine colitis models were employed to evaluate IRF5 function, incorporating cellular analyses from IRF5 knockout (KO) and wild-type mice. Clinical relevance was assessed using peripheral blood and intestinal specimens from UC patients.
RESULTS: IRF5 expression was elevated in G-MDSCs from colitic mice. IRF5 deficiency markedly increased G-MDSC frequency and immunosuppressive activity, while monocytic MDSCs (M-MDSCs) remained unaffected. Rescue experiments confirmed that IRF5 KO-derived G-MDSCs alleviated colitis severity. Mechanistically, ChIP-qPCR, luciferase reporter assays, and western blotting demonstrate that IRF5 represses S100A9 transcriptionally, thereby limiting G-MDSC accumulation. S100A9 is a Ca2+-binding protein that is critical for MDSC expansion. Clinically, UC patients demonstrated elevated IRF5 expression, which inversely correlated with circulating G-MDSC levels.
CONCLUSIONS: IRF5 acts as a transcriptional brake on G-MDSC development through S100A9 signaling, establishing the IRF5/G-MDSC axis as a novel pharmacological target for UC therapy.