Indole-3-Carboxaldehyde Alleviates LPS-Induced Intestinal Inflammation by Inhibiting ROS Production and NLRP3 Inflammasome Activation

Author:

Cao Ji12ORCID,Bao Qiuyu12,Hao Haiping12

Affiliation:

1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China

2. Key Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

Abstract

Indole-3-carboxaldehyde (IAld) is a tryptophan (Trp) metabolite derived from gut microbiota, which has a potential protective effect on intestinal inflammatory diseases. Abnormal activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an important cause of intestinal inflammation. However, the effect and mechanism of IAld on NLRP3 inflammasome activation remain unclear. Here, we found that IAld inhibited the activation of the NLRP3 inflammasome in intestinal epithelial cells, and effectively prevented intestinal epithelial barrier injury caused by lipopolysaccharide (LPS) stimulation. Mechanistically, we demonstrated that IAld activated the aryl hydrocarbon receptor (AhR), subsequently prevented reactive oxygen species (ROS) production, maintained mitochondrial membrane potential, and blocked the NF-κB/NLRP3 inflammatory pathway in intestinal epithelial cells. Also, the AhR-specific inhibitor CH-223191 effectively blocked the IAld-induced NLRP3 inhibition and intestinal epithelial barrier repairment. In addition, in vivo results showed that IAld prevented pro-inflammatory mediator production and intestinal inflammatory damage in LPS-induced mice, which is related to AhR activation and NLRP3 inflammasome inhibition. Collectively, our study unveiled that IAld is an effective endogenous antioxidant and suggested the AhR as a potential treatment target for NLRP3-induced intestinal inflammatory diseases.

Funder

National Natural Science Foundation of China

Project for Major New Drug Innovation and Development

Jiangsu Province Excellent Postdoctoral Program

Publisher

MDPI AG

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