Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability

Lee, J.S. et al. Immunity 43: 727-738, 2015

Speaker: Wei-Kuan Sung (宋惟寬)                      Time: 13:00~14:00 May 25, 2016

Commentator: Chung-Ta Lee (李忠達)                Place: Room 601

Abstract:

        Interleukin-17A (IL-17A) is the hallmark cytokine of the T helper (Th17) cell subset of CD4⁺ T cells, which have been implicated as the primary pathogenic population in a range of autoimmune disorders. IL-23 can promote the terminal differentiation and expansion of Th17 effector cells and is thought to orchestrate chronicity and severity in disease models, such as experimental autoimmune encephomyelitis (EAE) and inflammatory bowel disease (IBD). In Crohn’s disease (CD), single nucleotide polymorphisms (SNPs) in the IL23R locus are associated with disease susceptibility, and patients with active CD present with increased numbers of IL-23- and IL-17-expressing cells in the gut lamina propria. However, increasing evidence suggests opposing effects of the cytokines IL-23 and IL-17 in their contribution to intestinal immunopathology. Clinical trials have shown that anti-IL-23 monoclonal antibodies ameliorated IBD, whereas anti-IL-17 monoclonal antibodies exacerbated the disease. Although the clinical data fail to show any efficacy for neutralizing IL-17A or IL-17 receptor A (IL-17RA) in CD, the current understanding of the mechanism of IL-17-mediated protective effects in both mice and humans is lacking. Given the suggested role of IL-17A in maintaining barrier function of epithelial tissues, in this study the authors used knockout mice to investigate the potential protective effects of IL-17A on preserving epithelial integrity in a dextran sodium sulfate (DSS) model of acute colonic injury. The authors show that IL-17A could protect the mice from excessive gut permeability by signaling through the IL-17R adaptor protein Act-1 on epithelial cells. Moreover, γδ T cells were the major source of gut-protected IL-17 and are IL-23 independent. Neutralization of IL-23 dampened adaptive and innate cell activation while maintaining the production of protective IL-17A during epithelial injury. Furthermore, IL-17 regulated the cellular localization of the tight junction protein occludin and limited gut permeability. Taken together, these results suggest that IL-17-producing γδ T cells are important for the maintenance and protection of epithelial barriers in the intestinal mucosa against excessive permeability after injury.

References

1.         Huber, D. et al. Multiple dynamic representations in the motor cortex during sensorimotor learning. Nature 484: 473-478, 2012.

2.         Targan, S.R. et al. A randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of AMG 827 in subjects with moderate to severe Crohn's disease. Gastroenterology.143: e26, 2012.