NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-κB-Dependent and -Independent Functions

Katerina Vlantis, et al. Immunity 44: 553-567, 2016

Speaker: Wei-Kuan Sung (宋惟寬)                              Time: 13:00~14:00, October 19, 2016

Commentator: Dr. Chih-Peng Chang (張志鵬)            Place: Room 601

Abstract:

        The treatment of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is based on several different approaches relying on aminosalicylates, antibiotics, corticosteroids, and immunomodulatory agents, in addition to the newest biological agents. However, the mechanisms responsible for the initiation and chronicity of intestinal inflammation remain poorly understood^1,2. In this study, the authors took advantages of intestinal epithelial cells (IEC)-specific gene knockout mice, such as nuclear factor kB (NF-kB) essential modulator (NEMO), and other gene knockout mice, including Fas-associated via death domain protein (FADD), receptor-interacting protein kinase 1 (RIPK1), and RIPK3. The results show that IEC-specific ablation of NEMO caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. The authors also combined other gene knockout mice to investigate the role of NEMO in colitis. NEMO^IEC-KO mice combined RIPK1^-/- or FADD^-/- mice could, whereas NEMO^IEC-KO mice combined RIPK3^-/- mice could not, prevent epithelial cell death and Paneth cell loss. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.

References

1.         Blumberg, R. and Powrie, F. Microbiota, disease, and back to health: ametastable journey. Sci. Transl. Med. 4: 137rv7, 2012.

2.         Kaser, A., Zeissig, S. and Blumberg, R.S. Inflammatory bowel disease. Annu. Rev. Immunol. 28: 573-621, 2010.