Hyperuricemia Exacerbates Psoriatic Inflammation by Inducing M1 Macrophage Activation and Th1 Cell Differentiation

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Abstract

A higher prevalence of hyperuricemia is observed in psoriasis, yet the precise involvement of hyperuricemia in psoriasis remains unclear. Therefore, we investigated the relationship between hyperuricemia and psoriasis, as well as the potential mechanisms through which hyperuricemia may promote psoriatic inflammation. Firstly, a literature review on psoriasis and serum uric acid (SUA) levels and a retrospective analysis on PASI scores and SUA of 147 psoriasis patients at the Dermatology Hospital of Southern Medical University were performed. Then mouse models of hyperuricemia and psoriasis were established to assess the impact of hyperuricemia on psoriasis. Finally, assays examined monosodium urate (MSU) on macrophage M1 polarisation, Th1 differentiation and expressions of NLRP3 and ASC. The literature review indicated inconsistent SUA-psoriasis links; however, our clinical data indicated a positive correlation between PASI scores and SUA. Mouse model results indicated that hyperuricemia exacerbated psoriatic lesions and upregulated the transcription of inflammatory cytokines (IL-17A, IL-17F, IL-23A, IL-8, TNF-α and IL-1β) in skin lesions, effects which were reversed with allopurinol treatment. GO-BP, KEGG and GSEA enrichment analyses of RNA-seq data from mice skin lesions and spleens revealed increased enrichment of Toll-like receptor pathways, TNF-α signalling pathways and innate immune cell migration pathways. CIBERSORTx analysis showed increased M1 cell infiltration in skin lesions and Th1 differentiation in splenic lymphocytes under hyperuricemic conditions. In vitro, MSU enhanced IMQ or LPS-induced macrophage M1 polarisation and Th1 differentiation when co-cultured with M1 cells, which depends on TLR4 expression. In conclusion, hyperuricemia may exacerbate psoriasis by promoting macrophage M1 polarisation, increasing Th1 differentiation and psoriatic inflammation.

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