Role of innate lymphoid cells in chronic colitis during anti-IL-17A therapy.

IL-17A is an important cytokine in intestinal inflammation. However, anti-IL-17A therapy does not improve clinical outcomes in patients with Crohn's disease. We aimed to evaluate the role of RORγt innate lymphoid cells (ILCs) in murine colitis models in the absence of IL-17A. An acute colitis model was induced with either dextran sulfate sodium (DSS) or trinitrobenzenesulfonic acid (TNBS) and a chronic colitis model was induced by CD4CD45RB T cell transfer from either wild-type C57BL/6 or Il17a mice. An anti-IL-17A antibody, secukinumab, was also used to inhibit IL-17A function in the colitis model. Flow cytometry was performed to analyze the population of RORγt ILCs in the colonic lamina propria of mice with chronic colitis. Acute intestinal inflammation due to DSS and TNBS was attenuated in IL-17A knockout mice, whereas chronic colitis was not relieved by T cell transfer from Il17a mice (% of original body weight: wild-type mice vs. Il17a mice, 81.9% vs. 82.2%; P = 0.922). However, the mean proportion of LinRORγt lymphocytes was higher after T cell transfer from Il17a mice than that after T cell transfer from wild-type mice (28.8% vs. 18.5%). The proportion of LinRORγt was also increased in Rag2 mice that received T cell transfer from wild-type mice when anti-IL-17A antibody was administered (31.7%). Additionally, Il6 and Il22 tended to be highly expressed after T cell transfer from Il17a mice. In conclusion, RORγt ILCs may have an important role in the pathogenesis of chronic colitis in the absence of IL-17A. Blocking the function of IL-17A may upregulate Il6 and recruit RORγt ILCs in chronic colitis, thereby upregulating IL-22 and worsening the clinical outcomes of patients with Crohn's disease.