Corticotropin releasing hormone promotes inflammatory bowel disease via inducing intestinal macrophage autophagy

Sheng-Bing Zhao,Jia-Yi Wu,Tian Xia,Shu-Ling Wang,Zhao-Shen Li,Xin Chang,Yu Bai,Yi-Hang Song,Can Xu,Zi-Xuan He,Xue Fang

doi:10.1038/s41420-021-00767-8

Abstract

Psychosocial stress is a vital factor contributing to the pathogenesis and progression of inflammatory bowel disease (IBD). The contribution of intestinal macrophage autophagy to the onset and development of IBD has been widely studied. Herein, we investigated the underlying mechanism of psychosocial stress in an IBD mouse model pertaining to macrophage autophagy. Corticotropin releasing hormone (CRH) was peripherally administrated to induce psychosocial stress. For in vivo studies, dextran sulfate sodium (DSS) was used for the creation of our IBD mouse model. For in vitro studies, lipopolysaccharide (LPS) was applied on murine bone marrow-derived macrophages (BMDMs) as a cellular IBD-related challenge. Chloroquine was applied to inhibit autophagy. We found that CRH aggravated the severity of DSS-induced IBD, increasing overall and local inflammatory reactions and infiltration. The levels of autophagy in intestinal macrophages and murine BMDMs were increased under these IBD-related inflammatory challenges and CRH further enhanced these effects. Subsequent administration of chloroquine markedly attenuated the detrimental effects of CRH on IBD severity and inflammatory reactions via inhibition of autophagy. These findings illustrate the effects of peripheral administration of CRH on DSS-induced IBD via the enhancement of intestinal macrophage autophagy, thus providing a novel understanding as well as therapeutic target for the treatment of IBD.

Highlights

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a group of diseases characterized by the chronic and recurrent inflammation of intestinal mucosa [1, 2]
Chloroquine attenuated Corticotropin releasing hormone (CRH)-induced increases in inflammation and autophagy in bone marrow-derived macrophages (BMDMs) under the challenge of LPS we investigated whether CRH could induce an increase in inflammation via the process of autophagy in BMDMs under inflammatory loading in vitro
Here, we report for the first time that intestinal macrophage autophagy is highly associated with psychosocial stress and that it promotes the pathogenesis and progression of IBD

Summary

INTRODUCTION

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a group of diseases characterized by the chronic and recurrent inflammation of intestinal mucosa [1, 2]. Regulating macrophage-induced intestinal inflammatory and immune responses may be an effective approach in the treatment of IBD. Psychosocial stress has been reported to be a contributing factor in the pathogenesis and progression of IBD, eliciting damage to the intestinal defense system and disturbing microbial homeostasis [9,10,11]. Recent studies have revealed that peripheral CRH can play a key role in stress-induced intestinal disturbances. Abnormal or overwhelming induction of intestinal the LC3-II/I ratios in intestinal biopsy specimens from severe IBD macrophage autophagy has been reported to contribute to the patients were markedly higher. We hypothesize that psychosocial stress autophagy levels in IBD contributes to the aggravation of IBD through the enhancement High autophagy levels have been reported to play a role in the of intestinal macrophage autophagy. After 6 days of treatment with 3% DSS, we observed an increase in Beclin-1 levels, an increase in the LC3-II/I ratio, and a decrease in p62/SQSTM1 levels

RESULTS

DISCUSSION

MATERIALS AND METHODS

Findings

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