Small heat shock protein CRYAB inhibits intestinal mucosal inflammatory responses and protects barrier integrity through suppressing IKK\u03b2 activity

Weimin Xu,Mingxia Zhou,Long Cui,Xiaolei Wang,Yuegui Guo,Jinglue Song,Zhenyu Huang,Zhehui Zhu,Chen-Ying Liu,Yingwei Chen,Yili Yang,Zhanju Liu,Haoxin Zhao,Dongpeng Wen,Mingming Sun,Yuji Huang,Peng Du

doi:10.1038/s41385-019-0198-5

Abstract

Alpha B-crystallin (CRYAB) is an important member of the small heat shock protein family, and plays a protective and therapeutic role in neurological inflammation. CRYAB expression was assessed in cultured HT29 and Caco-2 cells and inflamed mucosa of patients with inflammatory bowel disease (IBD) and colitis models in mice. Lentivirus-overexpressing and CRSIPR/Cas9 systems were used in different cells to upregulate and silence CRYAB expression, respectively. Cell permeable recombined fusion protein TAT-CRYAB was injected intraperitoneally into dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice to assess its anti-inflammatory effects. CRYAB was found to be significantly decreased in the inflamed mucosa from IBD patients and DSS-induced colitis in mice, and negatively correlated with the levels of TNF-α and IL-6, respectively. Enforced expression of CRYAB suppressed expression of proinflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, and IL-8) via inhibiting the IKK complex formation, whereas lack of CRYAB expression markedly enhanced proinflammatory responses. Consistently, administration of TAT-CRYAB fusion protein significantly alleviated DSS- or TNBS-induced colitis in mice and protected intestinal barrier integrity. CRYAB regulates inflammatory response in intestinal mucosa by inhibiting IKKβ-mediated signaling and may serve as a novel therapeutic approach in the treatment of IBD.

Highlights

Inflammatory bowel disease (IBD) refers to the chronic inflammatory disease that affects the gastrointestinal tract, the most common forms were the ulcerative colitis (UC) and Crohn’s disease (CD).[1]
CRYAB expression is significantly decreased in inflamed colon from IBD patients To study the molecular mechanisms of CRYAB involved in the development and pathogenesis of IBD, we initially examined CRYAB expression in the inflamed colon from patients with active UC (A-UC) (n = 30) and active CD (A-CD) (n = 33) by Quantitative real-time PCR (qRT-PCR)
We observed that the expression of IL-6 and TNF-α was notably increased in the inflamed tissues of UC and CD (Fig. 1a), and that their levels were negatively correlated with the CRYAB expression in the inflamed colon from patients with A-CD

Summary

Introduction

Inflammatory bowel disease (IBD) refers to the chronic inflammatory disease that affects the gastrointestinal tract, the most common forms were the ulcerative colitis (UC) and Crohn’s disease (CD).[1] Noteworthily, the incidence rate of IBD has been increasing, in particular in the developing countries,[2] and the disease usually lasts for decades, characterized by alternating periods of the disease activity and remission,[3,4] emphasizing the urgent need for novel and more effective therapeutics. Several studies have reported that CRAYB plays protective and therapeutic roles in the development of neuroinflammation induced by injury, infection, neurodegeneration, and autoimmunity.[18,19,20,21,22]

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