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

  • Mucosal Immunol. 2019 Nov;12(6):1291-1303. doi: 10.1038/s41385-019-0198-5.
Weimin Xu   #  1 ,  Yuegui Guo   #  1 ,  Zhenyu Huang   #  1 ,  Haoxin Zhao  2 ,  Mingxia Zhou  3 ,  Yuji Huang  1 ,  Dongpeng Wen  1 ,  Jinglue Song  1 ,  Zhehui Zhu  1 ,  Mingming Sun  4 ,  Chen-Ying Liu  1 ,  Yingwei Chen  3 ,  Long Cui  1 ,  Xiaolei Wang  4 ,  Zhanju Liu  5 ,  Yili Yang  6 ,  Peng Du  7
Affiliations
  • 1. Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
  • 2. Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, 215123, China.
  • 3. Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China.
  • 4. Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
  • 5. Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China. [email protected].
  • 6. Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, 215123, China. [email protected].
  • 7. Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China. [email protected].
  • # Contributed equally.
PMID: 31481750 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.

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