Background/Purpose: Activation of fibroblast-like synoviocytes (FLS) by immune cells drives inflammation and joint damage in rheumatoid arthritis (RA). Hence, understanding factors that induce destructive behaviors in FLS is essential for developing new treatments for RA. While group 2 innate lymphoid cells (ILC2s) are present in the synovial tissue of RA patients, their specific role in RA pathogenesis and interaction with FLS are not well understood. This study uncovers a new pathogenic function of ILC2s in arthritis, demonstrating that modulating ILC2s can significantly influence RA progression. Additionally, ILC2s produce amphiregulin (AREG), a fibroblast-activating growth factor, which appears to play a role in their pathogenic mechanism.

Methods: Synovial ILCs were assessed in the K/BxN serum transfer-induced arthritis (STIA) and the active K/BxN models. Role of ILCs in arthritis was evaluated by subjecting Rag2-deficient (Rag2^-/-) and ILC-deficient (Rag2^-/-IL2rg^–) mice to STIA. ILC2s were ablated in (Rag2^-/- IL-5-Cre iDTR-floxed) mice using diphtheria toxin treatment and reconstituted from (IL-5-Cre tdTomato) donor mice into ILC-deficient mice to study arthritis progression. The role of ILC2-produced AREG in STIA was evaluated in AREG-KO mice and mice with conditional deletion of AREG in ILC2 (Rag2^-/- IL5-Cre Areg-floxed). Arthritis severity was assessed clinically and histologically. The effect of ILC2-derived cytokines on FLS migration was evaluated in vitro. Statistical differences were assessed using Mann-Whitney tests for area under the curve (AUC), in conjunction with analyses of gene expression and numerical variances.

Results: IL-5-producing ILC2s were enriched in arthritic synovium and were the predominant ILC subset in both active K/BxN (an increase of 670%; P=0.0001 vs. non-arthritic control) and STIA  (P=0.05 vs. non-arthritic control) models. ILC-deficient mice showed reduced STIA development compared to Rag2-deficient mice (AUC mean=7.4±3.9 vs. 17.2±4.3; P=0.03), indicating that ILCs promote arthritis development. ILC2 ablation ameliorated disease severity, and reconstitution of ILC-deficient mice with ILC2 exacerbated arthritis (AUC mean=19.2±3.2 vs. 10.3±6.0; P=0.01). ILC2-derived AREG was significantly increased in arthritic joints (P=0.0001 vs. non-arthritic control), and AREG-KO mice exhibited reduced arthritis severity (P=0.001 vs. littermate control). ILC2s are shown to be the major source of synovial AREG during arthritis, and conditional deletion of AREG in ILC2 resulted in reduced arthritis severity compared to WT littermate controls (AUC mean=30.4±1.2 vs. 45.0±6.1; P=0.0043). Mechanistically, ILC2 promoted activation of FLS (P=0.0001 vs control), an effect that could be inhibited by engaging the inhibitory receptor CD200R on ILC2

Conclusion: ILC2s are enriched and predominant in the arthritic joints of mice with K/BxN arthritis. ILC2-derived AREG exacerbates arthritis development and stimulates FLS activation and migration. Targeting the AREG-producing ILC2 signaling pathway could offer a novel therapeutic option for treating RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/group-2-innate-lymphoid-cells-aggravates-development-of-inflammatory-arthritis/