IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism.

Polymorphisms of interleukin (IL)-23R and signaling components are associated with several autoimmune diseases, including inflammatory bowel diseases (IBD). Similar to T helper type 17 (Th17) lineage, type 3 innate lymphoid cells (ILCs) express retinoic acid-related orphan receptor γt (Rorγt) and IL-23R and hence, produce Th17-type cytokines. Recent reports implicated type 3 ILCs in IBD; however, how IL-23R signaling in these cells contributes to pathogenesis is unknown. IL-22, produced in copious amounts by type 3 ILCs, was reported to have both beneficial and pathogenic effects in adaptive, yet only a protective role in innate colitis models. Herein, by employing chronic CD45RB(high) CD4(+) T-cell transfer and anti-CD40 antibody-induced acute innate colitis models in Rag1(-/-) mice, we demonstrated opposite roles for IL-23R in colitogenesis: in the former a protective, and in the latter a pathogenic role. Furthermore, we show that IL-23R signaling promotes innate colitis via IL-22 as neutralization of IL-22 protected mice from colitis and adding back of IL-22 to IL-23R-deficient animals restored the disease. Collectively, our results reveal that similar to its controversial role during chronic or adaptive colitis, IL-22 may also have opposite roles in innate colitis pathogenesis in a context and insult-dependent manner.