Dioscin ameliorates murine ulcerative colitis by regulating macrophage polarization

Area of Science:

• Immunology
• Pharmacology
• Cell Biology

Background:

• Ulcerative colitis (UC) treatment remains a challenge, with immune dysregulation, particularly macrophage polarization, being a key factor.
• Targeting macrophage polarization offers a promising therapeutic strategy for immune-mediated diseases like UC.
• Dioscin, a steroidal saponin, exhibits anti-inflammatory and immunomodulatory properties, suggesting potential therapeutic applications.

Purpose of the Study:

• To investigate the protective effects of Dioscin against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in a mouse model.
• To elucidate the underlying mechanisms of Dioscin's action, focusing on macrophage polarization and related signaling pathways.
• To explore Dioscin's impact on macrophage metabolism, including glycolysis and fatty acid oxidation (FAO).

Main Methods:

• Induction of colitis in mice using DSS and concurrent oral administration of Dioscin.
• In vitro polarization of RAW264.7 macrophages to M1 phenotype using lipopolysaccharide (LPS) and interferon-γ (INF-γ), followed by Dioscin treatment.
• Analysis of macrophage polarization (M1/M2), key signaling pathways (mTORC1/HIF-1α and mTORC2/PPAR-γ), and metabolic processes (glycolysis and FAO).
• Pharmacological inhibition of specific pathways (FAO, mTORC2, mTORC1) to confirm Dioscin's mechanism of action.

Main Results:

• Dioscin significantly ameliorated DSS-induced colitis in mice, reducing disease severity.
• Dioscin treatment decreased M1 macrophage polarization while markedly promoting M2 polarization in the colons of UC mice.
• In vitro, Dioscin inhibited the mammalian target rapamycin complex 1 (mTORC1)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway and restrained glycolysis.
• Concurrently, Dioscin activated the mammalian target rapamycin complex 2 (mTORC2)/peroxisome proliferator-activated receptor-γ (PPAR-γ) signal and facilitated fatty acid oxidation (FAO) in macrophages.
• Inhibition of FAO or mTORC2 signaling neutralized Dioscin's M2 polarization effect, while mTORC1 activation mitigated its M1 inhibitory effect.
• Specific pathway inhibitors and agonists blocked the therapeutic efficacy of Dioscin in vivo.

Conclusions:

• Dioscin demonstrates a protective effect against DSS-induced UC in mice, primarily by modulating macrophage polarization.
• Dioscin exerts its therapeutic effects by inhibiting M1 polarization and promoting M2 polarization of macrophages.
• The mechanism involves the regulation of mTORC1/HIF-1α signaling to restrain glycolysis and mTORC2/PPAR-γ signaling to facilitate FAO, thereby altering macrophage metabolism and polarization.
• Dioscin represents a potential therapeutic agent for UC, acting through the intricate regulation of immune cell metabolism and function.