Intervention of oncostatin M-driven mucosal inflammation by berberine exerts therapeutic property in chronic ulcerative colitis

Heng Li,Chunlan Feng,Xiaoqian Yang,Fenghua Zhu,Qiukai Lu,Wei Tang,Jianping Zuo,Peilan He,Zongwang Zhang,Chen Fan,Caigui Xiang,Yang Yang,Huimin Lu

doi:10.1038/s41419-020-2470-8

Abstract

Ulcerative colitis (UC) is a chronic and etiologically refractory inflammatory gut disorder. Although berberine, an isoquinoline alkaloid, has been revealed to exert protective effects on experimental colitis, the underlying molecular mechanism in chronic intestinal inflammation remains ill-defined. This study was designed to uncover the therapeutic efficacy and immunomodulatory role of berberine in chronic UC. Therapeutic effects of oral administration of berberine were investigated in dextran sodium sulfate (DSS)-induced murine chronic UC and the underlying mechanisms were further identified by si-OSMR transfection in human intestinal stromal cells. Berberine significantly attenuated the experimental symptoms and gut inflammation of chronic UC. Berberine treatment could also maintain the intestinal barrier function and rectify tissue fibrosis. In accordance with infiltrations of antigen-presenting cells (APCs), innate lymphoid cells (ILCs), and activated NK cells in colonic lamina propria, increased expression of OSM and OSMR were observed in the inflamed tissue of chronic UC, which were decreased following berberine treatment. Moreover, berberine inhibited the overactivation of human intestinal stromal cells through OSM-mediated JAK-STAT pathway, which was obviously blocked upon siRNA targeting OSMR. The research provided an infusive mechanism of berberine and illustrated that OSM and OSMR intervention might function as the potential target in chronic UC.

Highlights

Ulcerative colitis (UC), belonging to one form of inflammatory bowel diseases (IBD), is characterized by severe diarrhea, unintended weight loss, bloody stools, abdominal pain, and fatigue[1,2,3]
OSMR was mainly expressed on stromal cells, not immune cells and epithelial cells, and redundant Oncostatin M (OSM) further led to numerous inflammatory cells infiltrating to the mucosa, which pathologically contributed to intestinal fibrosis[13,15]
Berberine alleviated the inflammatory injury of DSSinduced chronic colitis In order to investigate the therapeutic capacity of berberine in chronic UC, experimental colitis was established by giving mice three cycles of 2% dextran sodium sulfate (DSS) in drinking water and berberine hydrochloride at the dose of 50 mg/kg was orally administrated daily from day 15 to the end point (Fig. 1a)

Summary

Introduction

Ulcerative colitis (UC), belonging to one form of inflammatory bowel diseases (IBD), is characterized by severe diarrhea, unintended weight loss, bloody stools, abdominal pain, and fatigue[1,2,3]. Li et al Cell Death and Disease (2020)11:271 have verified that recombinant OSM could induce the activation of JAK-STAT (including JAK1, JAK2, STAT1, STAT3, STAT4, STAT5, and STAT6), MAPK, and PI3KAKT pathways via the heterodimeric receptors comprised of OSMR and gp13013,15. Results from the colonic biopsies from IBD patients demonstrated that OSM and OSMR were highly expressed and positively correlated with the disease severity of Crohn’s diseases (CD) and UC15. OSMR was mainly expressed on stromal cells, not immune cells and epithelial cells, and redundant OSM further led to numerous inflammatory cells infiltrating to the mucosa, which pathologically contributed to intestinal fibrosis[13,15]. Targeting OSM and OSMR may provide new sights for understanding the underlying pathomechanism of UC and serve as an alternative therapeutic strategy[18,19]

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Conclusion