Background/Purpose: Transition from acute to chronic inflammation is a key step in the pathogenesis of inflammatory disease but incompletely characterized to date. Similar to the onset phase of inflammation, resolution of inflammation is actively regulated but coordinated by mediators diverse as those that initiate inflammation. Here we identified IL-9-producing Type 2 Innate lymphoid cells (ILC2s) as key regulators in the interaction between innate and adaptive immune responses that orchestrate resolution of inflammation in arthritis.

Methods: Wild-type and Il9 deficient mice were analyzed in three different models of arthritis, namely antigen induced arthritis (AIA), serum induced arthritis (SIA) and monosodium urate crystal (MSU) induced arthritis model, followed by histomorphometric analyses of inflammation, cartilage damage, bone damage, and micro-computed tomographies. For synovial tissue analyses (ILC2, IL-9-expressing cells) samples from untreated active RA patients (N=19) and RA patients in remission receiving treatment with DMARDs (methotrexate N=15, TNF inhibitors: N=5) were analyzed (N=19). In addition, a longitudinal biopsy cohort of 10 early (<12 months disease duration) RA patients receiving synovial biopsies at baseline and 6 months after start of anti-rheumatic therapy was analyzed. For the analysis of circulating ILC2s a cohort of 111 RA patients was analyzed. 63 of these 111 patients received a follow-up assessment of circulating ILC2s 6 to 12 months after baseline assessment.

Results: In the absence of IL-9, ILC2s did not proliferate and arthritis transformed into a chronic disease with persistent joint swelling, chronic synovial inflammation, excessive cartilage destruction and bone loss. Treatment with recombinant IL-9 led to proliferation and activation of ILC2s and promoted ILC2-dependent activation of regulatory T cells (Treg). This cell/cell contact dependent interaction between ILC2s and Tregs via GITR and ICOS resulted in suppression of Th17 driven inflammation and thereby also crucially influenced tissue damage and bone loss. The course of acute inflammation in response to MSU crystals was not affected by IL-9. IL-9-producing ILC2s increased during resolution of RA both in the synovial membrane as well as in the peripheral blood. IL-9+ ILC2 counts were very low in the synovium of active RA patients, in whom IL-9 production was mostly confined to lineage (Lin) positive cells. In contrast, RA patients in remission (DAS28 < 2.6) showed a strong upregulation of Lin- IL-9+ ILC2s. Also the longitudinal analysis of synovial tissue of RA patients showed a switch of the cellular source of IL-9 from Lin+ IL-9+ cells during active disease to Lin- IL-9+ ILC2s after successful treatment with anti-rheumatic drugs over 6 months.

Conclusion: IL-9 driven activation of ILC2s might thus provide a novel therapeutic anchor to induce resolution of chronic inflammatory disease such as arthritis and to restore immune homeostasis. Current cytokine-targeting strategies exclusively suppress the activation pathways rather than fostering resolution of disease, our data provide evidence for a new concept in inflammatory medicine by modifying cytokine pathways relevant for resolution of inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-9-producing-innate-lymphoid-cells-keyplayers-that-orchestrate-resolution-of-chronic-inflammation-in-arthritis/