Integrative analysis reveals the multilateral inflammatory mechanisms of CD14 monocytes in gout

医学 痛风 CD14型 免疫学 炎性关节炎 炎症 单核细胞 关节炎 生物信息学 内科学 免疫系统 生物
作者
Ahmed Alaswad,Georgiana Cabău,Tania O. Crişan,Liang Zhou,Martijn Zoodsma,Javier Botey-Bataller,Wenchao Li,Cristina Pamfil,Mihai G. Netea,Tony R. Merriman,Cheng‐Jian Xu,Li Yang,Leo A. B. Joosten
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
标识
DOI:10.1016/j.ard.2025.01.046
摘要

Gout, prevalent inflammatory arthritis caused by urate crystal deposition, involves immune cell activation, yet the precise role of CD14 monocytes in initiating the inflammatory response is poorly understood. This study aimed to characterise the molecular and cellular landscape of CD14 monocytes in gout using single-cell transcriptomic analysis. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells from 8 gout patients and 6 age- and sex-matched healthy controls. The findings were validated using publicly available datasets. Differential gene expression and pathway enrichment analyses were conducted to identify gout's key molecular regulators and cellular subclusters. At the molecular level, we identified hypoxia-related pathways, including HIF1A, as key regulators of interleukin-1β production in CD14 monocytes in gout. We also observed significant downregulation of CLEC12A across all CD14 monocyte subclusters. At the cellular level, an S100Ahigh CD14 monocyte subcluster, characterized by high expression of S100A8/A9/A12 and linked to inflammatory and metabolic pathways, was found to drive NLRP3 and CLEC7A inflammasome activation, as well as prostaglandin secretion. In vitro stimulation with monosodium urate crystals revealed that the differentially expressed genes were enriched in S100Ahigh monocytes, highlighting the synergistic role of these pathways in driving gout inflammation. Additionally, gout genome-wide association study-prioritised genes underscored the role of fatty acid metabolism in inflammation, promoting prostaglandin secretion from S100Ahigh monocytes. These findings provide new insights into the role of CD14 monocytes in gout pathogenesis, particularly the contribution of hypoxia and fatty acid metabolism pathways, and suggest potential therapeutic targets for precision medicine in gout treatment.
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