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Anemoside B4 alleviates DSS-induced colitis by inhibiting CD1d-dependent NLRP3 inflammasome activation in macrophages
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  • jiao Li,
  • Pan Li,
  • Shuo Yuan,
  • Jia-Chen Xue,
  • Huan Meng,
  • Xiao-Ting Hou,
  • Bi-Hu Gao,
  • Qinggao Zhang
jiao Li
Affiliated Zhongshan Hospital of Dalian University
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Pan Li
City University of Hong Kong
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Shuo Yuan
Yanbian University
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Jia-Chen Xue
Affiliated Zhongshan Hospital of Dalian University
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Huan Meng
Dalian University
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Xiao-Ting Hou
Dalian University
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Bi-Hu Gao
Affiliated Zhongshan Hospital of Dalian University
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Qinggao Zhang
Dalian University

Corresponding Author:[email protected]

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Abstract

Background and Purpose: Abnormal activation of the NLRP3 inflammasome in macrophages is closely associated with Ulcerative colitis (UC), and targeting the NLRP3 inflammasome has been proposed as a potential therapeutic approach, but the underlying mechanism by which it regulates intestinal inflammation remains unclear. Anemoside B4 (AB4) has anti-inflammatory activity, but whether it alleviates UC by inhibiting the activation of NLRP3 inflammasome remains unclear. More importantly, the molecular targets of AB4 remain unknown. Experimental Approach: We explored the role of AB4 in the development of dextran sodium sulfate (DSS)-induced colitis in wild-type (WT) mice and its effect on NLRP3 inflammasome. We isolated intestinal macrophages and epithelial cells, and validated them in DSS-induced NLRP3-deficient (NLRP3-/-) mice. The target and molecular mechanism of AB4 were identified in LPS-induced macrophages in vitro and DSS-induced macrophage-specific CD1d depletion (CD1d-/-) mice in vivo. Key Results: This study showed that AB4 had a strong anti-inflammatory effect DSS-induced colitis in WT mice, whereas the protective effects were lost in NLRP3-/- mice. AB4 inhibited the activation of NLRP3 inflammasome in colonic macrophages without affecting intestinal epithelial cells. Mechanistically, AB4 might target CD1d thus reducing the AKT-STAT1-PRDX1-NF-κB signaling pathway, eventually inhibiting the activation of NLRP3 inflammasome. Macrophage-specific CD1d depletion had been shown to reverse the protective effect of AB4. Conclusions and Implications: Our data showed that AB4 attenuated DSS-induced colitis by inhibiting CD1d-dependent NLRP3 inflammasome activation in macrophages. Therefore, as a natural product with high safety index, AB4 might be considered a promising candidate drug for the treatment of colitis.
12 Sep 2023Submitted to British Journal of Pharmacology
14 Sep 2023Submission Checks Completed
14 Sep 2023Assigned to Editor
14 Sep 2023Review(s) Completed, Editorial Evaluation Pending
16 Sep 2023Reviewer(s) Assigned
10 Oct 2023Editorial Decision: Revise Minor