Ying‐Ping Xu

Immunosenescence is a result of progressive decline in immune system function with advancing age. Epidermal Langerhans cells (LCs), belonging to the dendritic cell (DC) family, act as sentinels to play key roles in the skin immune responses. However, it has not been fully elucidated how aging affects development and function of LCs. Here, we systemically analyzed LC development and function during the aging process in C57BL/6J mice, and performed global microRNA (miRNA) gene expression profiles in aged and young LCs. We found that the frequency and maturation of epidermal LCs were significantly reduced in aged mice starting at 12 months of age, while the Langerin expression and ability to phagocytose Dextran in aged LCs were increased compared to LCs from < 6 month old mice. The migration of LCs to draining lymph nodes was comparable between aged and young mice. Functionally, aged LCs were impaired in their capacity to induce OVA-specific CD4+ and CD8+ T cell proliferation. Furthermore, the expression of miRNAs in aged epidermal LCs showed a distinct profile compared to young LCs. Most interestingly, aging-regulated miRNAs potentially target TGF-β-dependent and non- TGF-β-dependent signal pathways related to LCs. Overall, our data suggests that aging affects LCs development and function, and that age-regulated miRNAs may contribute to the LC developmental and functional changes in aging.

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that repress target genes at post-transcriptional level. Langerhans cells (LCs) are skin-residential dendritic cells (DCs) with a life cycle distinct from other types of DCs. miRNA deficiency interrupts the homoeostasis and function of epidermal LCs, suggesting the critical roles of miRNAs in LC development and function. However, the roles of individual miRNAs in regulating LC development and function remain completely unknown. MiRNA miR-150 is highly expressed in mature lymphocytes and regulates T- and B-cell development and function. Here, we reported that miR-150 is also expressed in epidermal LCs, and its expression is significantly down-regulated during in vitro LC maturation. Using a miR-150 knockout mouse model, we found that lack of miR-150 reduces the capacity of LCs to cross-present a soluble antigen to antigen-specific CD8(+) T cells, but does not disturb the development, maturation, migration and phagocytic capacity of LCs. Thus, our data indicate that miR-150 is required for LC cross-presentation.

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.