Background/Purpose: The interleukin-17 (IL-17) family of cytokines consists of 6 evolutionarily conserved cytokines, IL-17A-F. Of these, IL-17A, B, C, and F play diverse roles in homeostasis and inflammation. IL-17A plays a critical pro-inflammatory role in inflammatory arthritis, particularly in the spondyloarthritis (SpA) spectrum of disease. IL-17D is an understudied member of the IL-17 family of cytokines and its function appears to be context dependent. We sought to identify the role of IL-17D in inflammatory arthritis.

Methods: We utilized two models of inflammatory arthritis: the SKG model and the serum transfer arthritis (STA) model. We tested the effect of recombinant IL-17D treatment on arthritis development in both the STA and SKG models of arthritis and assessed clinical inflammation and expression of pro-inflammatory factors in the paws by qPCR. We induced STA in Il17d-deficient mice and controls, performed histology and assessed cytokines by Luminex.

To identify the cell types expressing IL-17D in inflamed synovial tissues from patients with SpA and RA, we analyzed single-cell sequencing data from the Accelerating Medicines Partnership (AMP I) database, and performed RNAscope and immunofluorescence (IF). Finally, we performed in vitro stimulation experiments using primary human cells and cell lines.

Results: We have previously reported that IL-17D is the most highly expressed IL-17 family member in synovial tissue at the transcriptional level in patients with SpA and its expression correlates inversely with inflammation. Il17d-deficient mice develop more severe arthritis than littermate controls. We now show that treatment of arthritic mice with recombinant IL-17D protein attenuates inflammation in both the STA and SKG murine models of inflammatory arthritis, accompanied by downregulation of pro-inflammatory cytokines. In inflamed human synovial tissues, IL-17D mRNA is most highly expressed in CD34+ Fibroblast-like synoviocytes (FLS) that also express markers of stromal cell progenitors. Single-cell analysis and IF revealed the presence of one previously identified receptor for IL-17D, CD93, in inflamed synovial tissues.

Conclusion: IL-17D and the CD93 receptor are expressed in inflamed synovial tissues. IL-17D expression is localized to CD34+ FLS. In contrast to other IL-17 family cytokines that are pro-inflammatory, IL-17D attenuates inflammation in two animal models of arthritis. This finding is confirmed in the IL-17D-deficient setting. These data support an anti-inflammatory role for IL-17D in inflammatory arthritis. Further studies are ongoing to define the mechanism by which the IL-17D pathway impacts inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-stromal-cell-derived-cytokine-interleukin-17d-attenuates-joint-inflammation/