Background/Purpose: Interleukin(IL)-17D is a little recognized member of the IL-17 family of cytokines. While the activities of IL-17A and IL-17F in the pathogenesis of spondyloarthritis (SpA) are established, a role for IL-17D in SpA and tissue inflammation has not yet been demonstrated.

Methods: In order to identify the cell types that express IL-17D in SpA synovial tissue and in primary human cells, we performed RNA sequencing, qPCR and IF analyses. We isolated fibroblast-like synoviocytes (FLS) from inflamed SpA synovial tissues, and stimulated cultured FLS with cytokines or subjected FLS to osteogenic differentiation. To determine a potential role for IL-17D in bone, femurs from il17d^-/- mice were assessed by micro-computed tomography analysis. Serum transfer arthritis (STA) was also induced in il17d^-/- mice and we performed subsequent Luminex assays to assess circulating cytokine expression at peak inflammation.

Results: In SpA inflamed synovial tissues, we demonstrate that IL-17D mRNA is more highly expressed than any other IL-17 family member, and that IL-17D is expressed by FLS that stain positive for markers of multipotent mesenchymal stromal cells (MSCs). In vitro, FLS express IL-17D at baseline. Osteogenic differentiation upregulates IL-17D mRNA in FLS when differentiated to osteoblast-like cells. In vivo, cells with the morphologic appearance of osteoblasts in bone sections also express IL-17D. However, Il17d^-/- mice fail to demonstrate a bone phenotype, suggesting that IL-17D deletion does not impact bone homeostasis. Importantly, there is an inverse correlation between IL-17D expression and inflammation in vitro and in vivo. Anti-IL-17A treatment in SpA patients decreases synovial inflammation, and correlates with an increase in synovial IL-17D mRNA expression. Additionally, Il17d^-/- mice demonstrate a more severe arthritis than littermate controls, and show elevated levels of pro-inflammatory cytokines at peak inflammation in STA, including TNFα, MCP-1 and MIP-1α.

Conclusion: These data demonstrate that IL-17D is the most highly-expressed IL-17 family member in inflamed SpA synovium. We localized IL-17D expression to stromal cells, including FLS. Furthermore, IL-17D expression is downregulated during human and experimental SpA inflammation, and evidence from STA indicates that this cytokine may exert an anti-inflammatory effect on joint inflammation.

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