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-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 induced serum transfer arthritis (STA) in IL-17D–deficient mice and controls and assessed clinical inflammation and cytokine expression by Luminex. We tested the effect of IL-17D in the development of inflammatory arthritis in both the STA and SKG models of arthritis. We assessed clinical inflammation and expression of pro-inflammatory factors in the paws by qPCR. We used the recently published single-cell RNA-seq atlas of inflamed synovium in rheumatoid arthritis (RA) patients (1) to identify the cell states expressing IL-17D. We used high-dimension transcriptomics data obtained by spatially profiling inflamed RA synovial tissues using CosMx and Xenium to map these IL-17D-expressing cells in situ. We performed colocalization analysis to identify statistically significant cell-cell interactions. We performed RNAscope and immunofluorescence (IF) to validate the results.

Results: IL-17D-deficient mice develop more severe arthritis than littermate controls. We 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. IL-17D’s expression in human synovial tissue inversely correlates with local and systemic inflammation in RA patients. In RA synovial tissue, IL-17D mRNA is the most highly expressed in CD34+ stromal cells, which also express markers of stromal cell progenitors. Spatial transcriptomics profiling of inflamed RA synovium reveals that IL-17D+CD34+ stromal cells significantly colocalize with MERTK+SELENOP+LYVE1+ monocytes. Single-cell analysis and IF reveal the presence of one previously identified receptor for IL-17D, CD93, in inflamed synovial tissues.

Conclusion: IL-17D attenuates inflammation in two animal models of arthritis, and this finding is confirmed in the IL-17D-deficient setting. IL-17D and one receptor for IL-17D, CD93, are expressed in the inflamed RA synovial tissue. Although IL-17A and F are produced mainly by lymphocytes, IL-17D expression localizes to CD34+ stromal cells. The co-localization of IL-17D+CD34+ stromal cells with anti-inflammatory MERTK+SELENOP+LYVE1+ monocytes supports a potential interaction between these cell types to regulate inflammation. These data support a unique function of IL-17D among IL-17 family members by demonstrating an anti-inflammatory role for IL-17D in inflammatory arthritis.

References: 1) Zhang, F., Jonsson, A.H., Nathan, A. et al. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature 623, 616–624 (2023).

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-stromal-cell-derived-cytokine-interleukin-17d-attenuates-joint-inflammation-2/