Inhibition of corticotropin-releasing hormone receptor 1 and activation of receptor 2 protect against colonic injury and promote epithelium repair

Bo Li,Richard You Wu,Tanja Gonska,Elke Zani-Ruttenstock,Lijun Chi,Tali Filler,Paul Delgado-Olguin,Carol Lee,Pekka Määttänen,Shigang Chen,Wan Ip,Philip M Sherman,Agostino Pierro,Yuhki Koike,Augusto Zani,Alison Hock,Qi Li

doi:10.1038/srep46616

Abstract

Maternal separation (MS) in neonates can lead to intestinal injury. MS in neonatal mice disrupts mucosal morphology, induces colonic inflammation and increases trans-cellular permeability. Several studies indicate that intestinal epithelial stem cells are capable of initiating gut repair in a variety of injury models but have not been reported in MS. The pathophysiology of MS-induced gut injury and subsequent repair remains unclear, but communication between the brain and gut contribute to MS-induced colonic injury. Corticotropin-releasing hormone (CRH) is one of the mediators involved in the brain–gut axis response to MS-induced damage. We investigated the roles of the CRH receptors, CRHR1 and CRHR2, in MS-induced intestinal injury and subsequent repair. To distinguish their specific roles in mucosal injury, we selectively blocked CRHR1 and CRHR2 with pharmacological antagonists. Our results show that in response to MS, CRHR1 mediates gut injury by promoting intestinal inflammation, increasing gut permeability, altering intestinal morphology, and modulating the intestinal microbiota. In contrast, CRHR2 activates intestinal stem cells and is important for gut repair. Thus, selectively blocking CRHR1 and promoting CRHR2 activity could prevent the development of intestinal injuries and enhance repair in the neonatal period when there is increased risk of intestinal injury such as necrotizing enterocolitis.

Highlights

Maternal separation (MS) in neonates can lead to intestinal injury
Antalarmin, but not Astressin-2β, prevented the maternal separation (MS)-induced elevation in pro-inflammatory cytokines (Fig. 1E–G). These results confirm that MS induces an increase in pro-inflammatory cytokines via Corticotropin-releasing hormone (CRH), which can be inhibited by blocking CRHR1
We have demonstrated that treatment with the CRHR1 antagonist Antalarmin protects against colonic injury following MS by preventing changes in colonic morphology, inflammation, permeability and microbiota

Summary

Introduction

Maternal separation (MS) in neonates can lead to intestinal injury. MS in neonatal mice disrupts mucosal morphology, induces colonic inflammation and increases trans-cellular permeability. We have previously shown that MS in neonatal mice changes the intestinal mucosal morphology, increases trans-cellular permeability and causes colonic inflammation[4,5,6]. CRHR1 promotes intestinal inflammation and angiogenesis in an animal model of colitis, but the effects of CRHR1 are reversed by CRHR2 activation[19] This suggests a dual role of CRH in regulating mucosal injury. Our study aims to distinguish the roles of CRHR1 and CRHR2 in MS-induced intestinal injury and repair during early postnatal life (postnatal days 5–9) in mice. This knowledge will facilitate the design of experimental treatments and prevention strategies for neonatal intestinal injury

Methods

Results

Conclusion