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

Abstract

SummaryDespite 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.

Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

“…Our recent study with SKG mice has addressed which GM‐CSF–producing cells are critical for arthritis development and how GM‐CSF production is regulated in each population. Effector Th17 cells in the arthritic joints co‐produced IL‐17 and GM‐CSF and augmented arthritis . In addition, unexpectedly, it was non‐CD4 + T cell–derived GM‐CSF that was indispensable for arthritis progression.…”

“…In response to CCL20, CCR6 + effector Treg cells also accumulate in inflamed tissues such as arthritic joints of SKG mice; yet, it is still unclear how a subset of effector Treg cells express particular chemokine receptors and specifically downregulate chronic tissue inflammation . In addition, the activated FLSs not only mediate synovitis and bone destruction themselves, but also recruit abundant neutrophils to the joints by producing chemokines such as CXCL1 and CXCL5 . IL‐6 abundantly produced by FLSs, and macrophages may promote further Th17 cell differentiation, while IL‐2 from activated T cells may inhibit the differentiation .…”

“…Activated CCR6 + Th17 cells migrate into the joints in a CCR6-CCL20 axis-dependent manner mediate synovitis and bone destruction themselves, but also recruit abundant neutrophils to the joints by producing chemokines such as CXCL1 and CXCL5. 58 IL-6 abundantly produced by FLSs, and macrophages may promote further Th17 cell differentiation, while IL-2 from activated T cells may inhibit the differentiation. [84][85][86] In the inflamed synovial tissue of human RA, Th17 cells and FLSs express CCR6 and CCL20, respectively, with a positive correlation between the levels of IL-17 and CCL20.…”

“…produced by arthritogenic Th17 cells is responsible for triggering the initial synovial inflammation, our recent work has revealed that GM-CSF, produced by arthritogenic Th17 cells, innate lymphoid cells (ILCs), and FLSs, plays a critical role in the maintenance of the chronic phase of synovial inflammation. 58 GM-CSF can be produced by various types of immune and non-hematopoietic cells including T cells and fibroblasts, and is known to be a potent activator of monocytes, macrophages, and DCs to produce proinflammatory cytokines such as IL-6 and TNF-α. 88 GM-CSF has been implicated in RA pathogenesis and considered as a potential therapeutic target because GM-CSF is abundant in the synovial fluid of RA patients and associated with activation of synovial macrophages to produce high levels of IL-6 and TNF-α in severe inflammation.…”

Targeting granulocyte‐monocyte colony‐stimulating factor in psoriasis. What a negative study can teach us

“…Importantly, GM‐CSF contributes to the differentiation and pathogenesis of T‐helper (Th)17 cells . GM‐CSF also appears to be induced by Th17 cells in a model of autoimmune arthritis . Thus, there is a scientific basis for GM‐CSF as a target in psoriasis and psoriatic arthritis.…”