Oxypalmatine alleviates ulcerative colitis through RAB8A-mediated inhibition of STAT1-driven pro-inflammatory macrophage polarization.
TL;DR
OPAL significantly ameliorated DSS-induced colitis by reducing colon shortening, weight loss and intestinal barrier damage, which relied on the inhibition on M1 polarization as confirmed by flowcytometry and macrophage-depletion.
Abstract
Background
Ulcerative colitis (UC) is a type of inflammatory bowel disease. Macrophage polarization is crucial in the development of UC. Oxypalmatine (OPAL) is an isoquinoline alkaloid that can be isolated from various plant, including Phellodendron amurense and Sinomenium acutum. It is also an oxidative metabolite derived from the hepatic biotransformation of palmatine (PAL), which is one of the active constituents of Coptis chinensis that demonstrates anti-inflammatory and antioxidant properties.
Purpose
This study aimed to explore the anti-inflammatory properties of OPAL and the mechanisms involved.
Methods
Efficacy of OPAL and its impact on macrophage polarization were assessed in a dextran sodium sulfate (DSS)-induced mouse model of colitis. Necessity of macrophage in the alleviation by OPAL was confirmed with a macrophage-depletion model. Transcriptomics analysis was performed on the colon to identify the corresponding signaling pathways. In an in vitro model of THP-1-derived macrophage, the effect of OPAL was assessed in terms of cell energy metabolism, cytokines production, and epithelium damage. Target of OPAL was explored by limited proteolysis-mass spectrometry (LiP-MS) analysis and siRNA-mediated knockdown.
Results
OPAL significantly ameliorated DSS-induced colitis by reducing colon shortening, weight loss and intestinal barrier damage, which relied on the inhibition on M1 polarization as confirmed by flowcytometry and macrophage-depletion. In vitro, OPAL suppressed the inflammatory response in THP-1-derived macrophages, and reprogrammed the energy metabolism profile by reducing the glycolysis and enhancing basal respiration and maximal respiration. Mechanistically, OPAL inhibited M1 polarization via suppressing the JAK-STAT signaling pathway, which mainly relied on binding to RAB8A protein to suppress STAT1 phosphorylation and the consequent HK2 expression.
Conclusion
OPAL ameliorated UC by suppressing M1 macrophage polarization via the RAB8A/STAT1 axis, highlighting a promising treatment strategy for UC management.