Autoimmune Th17 Cells Induced Synovial Stromal and Innate Lymphoid Cell Secretion of the Cytokine GM-CSF to Initiate and Augment Autoimmune Arthritis

Despite the importance of Th17 cells in autoimmune diseases, it remains unclear how they control other inflammatory cells in autoimmune tissue damage. Using a model of spontaneous autoimmune arthritis, we showed that arthritogenic Th17 cells stimulated fibroblast-like synoviocytes via interleukin-17 (IL-17) to secrete the cytokine GM-CSF and also expanded synovial-resident innate lymphoid cells (ILCs) in inflamed joints. Activated synovial ILCs, which expressed CD25, IL-33Ra, and TLR9, produced abundant GM-CSF upon stimulation by IL-2, IL-33, or CpG DNA. Loss of GM-CSF production by either ILCs or radio-resistant stromal cells prevented Th17 cell-mediated arthritis. GM-CSF production by Th17 cells augmented chronic inflammation but was dispensable for the initiation of arthritis. We showed that GM-CSF-producing ILCs were present in inflamed joints of rheumatoid arthritis patients. Thus, a cellular cascade of autoimmune Th17 cells, ILCs, and stromal cells, via IL-17 and GM-CSF, mediates chronic joint inflammation and can be a target for therapeutic intervention. [Display omitted] •T cell production of GM-CSF is dispensable for the initiation of arthritis•GM-CSF from stromal cells is crucial for the initiation of autoimmune arthritis•GM-CSF-producing synovial-resident ILCs augment autoimmune arthritis•ILC production of GM-CSF is stimulated by IL-2, IL-33, or TLR9 ligands It remains obscure how joint inflammation in rheumatoid arthritis is initiated and progressing. In this study, Hirota et al. identified in an animal model of rheumatoid arthritis an inflammatory cellular cascade instigated by an arthritogenic T helper subset and enhanced by GM-CSF-producing synovial-resident innate lymphoid cells.