Background/Purpose: Interleukin-23 (IL-23) and its cognate receptor interleukin-23R (IL-23R):IL-12Rβ1 plays a critical role in the pathogenesis of autoimmune diseases including psoriasis and psoriatic arthritis. Although significance of IL-23 signaling in adaptive immunity has been well-studied, the role of IL-23 in myeloid cell activation remains unknown.

Methods: To investigate role of CLEC5A/MDL-1 in psoriatic arthritis-like pathology, we performed in vivo gene transfer of IL-23 in WT, IL-23R^GFP reporter, and Mdl-1^-/- mice. qRT-PCR, RNAseq, Western blot, flow cytometry, ELISA, H&E stain, and immunofluorescence staining methods were used to analyze the phenotype of WT and transgenic mice.

Results: Herein, we show in the IL-23R^GFP reporter mice, that IL-23 induces the expansion of myeloid cell populations including an epidermal myeloid DNAX activation protein 12 (DAP12)-associating lectin-1 (MDL-1)⁺CD11b⁺Ly6G⁺IL-23R⁺ cell population associated with epidermal hyperplasia and an MDL-1⁺CD11b⁺Ly6C^highIL-23R⁺ associated with bone destruction. Mechanistically, genetic ablation of MDL-1 prevented IL-23-gene transfer elicited myelopoiesis and showed a marked reduction of skin inflammation markers (K16, S100a7, S100a8, S100a9, Cxcl-1, Cxcl-2) and bone destruction markers (Acp5, Ctsk, Mmp9) compared to wildtype mice. Moreover, we found that Mdl-1^-/- mice had significantly higher bone mass and impaired osteoclast differentiation in vitro and in vivo as well as reduced joint inflammation in IL-23 gene transfer induced arthritis. Mechanistic data through of flow cytometry, Western blotting and co-immunoprecipitation experiments revealed that a trimeric complex of IL-23R/DAP12/MDL-1 elicited the associated pathologies in our murine model. Furthermore, we performed RNAseq analysis of murine skin following IL-23 gene transfer and revealed 297 differentially expressed genes (DEGs) affected by MDL-1 deletion. Specifically, these DEGs are associated with myelopoiesis, neutrophil proteases, DAP12, cell survival and apoptosis. We correlated our findings with RNAseq meta-analyses derived from human psoriatic skin (135 patients vs 133 controls), which showed elevation of MDL-1 in psoriatic patients and positive correlation for IL-23 versus MDL-1 and IL-23R versus MDL-1.

Conclusion: Collectively, our data demonstrate that MDL-1 is a critical component of IL-23 signaling that dictates synovial and skin inflammation in vivo, and could be targeted for the treatment of PsA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/clec5a-mdl-1-is-critical-for-inflammatory-arthritis-and-skin-inflammation/