1. Academic Validation
  2. Antagonizing interleukin-5 receptor ameliorates dextran sulfate sodium-induced experimental colitis in mice through reducing NLRP3 inflammasome activation

Antagonizing interleukin-5 receptor ameliorates dextran sulfate sodium-induced experimental colitis in mice through reducing NLRP3 inflammasome activation

  • Eur J Pharmacol. 2024 Jan 14:965:176331. doi: 10.1016/j.ejphar.2024.176331.
Yitao Ou 1 Zhongjin Yang 1 Yinghua Zhou 1 Hu Yue 1 Lei Hua 1 Zhuorong Liu 1 Geng Lin 1 Haowei Cai 1 Yanhong Chen 1 Wenhui Hu 2 Ping Sun 3
Affiliations

Affiliations

  • 1 The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • 2 The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address: huwenhui@gzhmu.edu.cn.
  • 3 The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address: sun_ping@gzhmu.edu.cn.
Abstract

Inflammatory bowel disease (IBD) is a condition characterized by inflammation in the gastrointestinal tract. Reducing intestinal inflammation is a promising approach for treating IBD. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, a critical component of the innate immune system, is implicated in the pathogenesis of IBD. Therefore, inhibiting NLRP3 inflammasome activation is a potential therapeutic strategy for IBD. In this study, we investigated the effects of the interleukin-5 (IL-5) receptor antagonist YM-90709 on dextran sulfate sodium-induced experimental colitis in mice. We found that YM-90709 reduced the expressions of IL-1β and Caspase-1 p20 in the colon and ameliorated colitis. Furthermore, we identified YM-90709 as an effective agent for inhibiting NLRP3 inflammasome activation. Knockdown of IL-5 Receptor or using an inhibitor of STAT5, a key transcription factor downstream of the IL-5/IL-5 Receptor signal pathway, also reduced NLRP3 inflammasome-dependent IL-1β release and ASC speck formation. Our study is the first to demonstrate that the NLRP3 inflammasome may be a downstream signal of IL-5/IL-5 Receptor and that YM-90709 protects against IBD by inhibiting IL-5 Receptor. These findings suggest a new strategy for regulating intestinal inflammation and managing IBD.

Keywords

ASC speck; Inflammatory bowel disease; Interleukin-5 receptor; NLRP3 inflammasome; YM-90709.

Figures
Products