Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cells

作者：Yimei Lai, Lili Zhuang, Jieying Zhu, Shuang Wang, Chaohuan Guo, Binfeng Chen, Jin Li, Jia Shi, Mengyuan Li, Niansheng Yang, Mianjing Zhou · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05951-9 · 被引用次数：13 · 研究领域：Inflammasome and immune disorders、Systemic Lupus Erythematosus Research、Immune Cell Function and Interaction

Renal CD8 + tissue-resident memory T (T RM ) cells display prolonged survival and activity in lupus nephritis (LN), exacerbating renal pathology. NLRP3 regulates the T cell response. This study explored the impact of NLRP3 inflammasome activity on the regulatory functions of T RM cells in LN. NLRP3 inflammasome activity in renal CD8 + T RM cells from lupus-prone MRL/lpr mice and in vitro induced human CD8 + CD103 + T cells was assessed by quantifying NLRP3, caspase-1, gasdermin D (GSDMD), and IL-1β levels using flow cytometry, ELISA, and western blotting analysis. The specific NLRP3 inhibitor MCC950, caspase-1 inhibitor Ac-YVAD-cmk, and NF-κB inhibitor JSH23 were utilized to delineate the role of NLRP3 in modulating the pathogenicity of CD8 + T RM cells in LN. Activation of the NLRP3 inflammasome was confirmed in renal CD8 + CD69 + CD103 + T RM cells derived from mice with LN and in vitro-induced human CD8 + CD103 + T RM -like cells. MCC950 curtailed the infiltration and activity of CD8 + CD69 + CD103 + T RM cells and enhanced renal outcomes. MCC950 also suppressed the maturation and functional capabilities of CD8 + CD103 + T cells in a manner reliant on inflammasome activity in vitro. IL-1β promoted the expression of TGF-βRII in CD8 + T cells via the NF-κB pathway. NLRP3 inflammasome activity in renal CD8 + CD69 + CD103 + T RM cells contributes to LN pathogenesis by regulating cell differentiation and effector functions. Therapeutically targeting the NLRP3 inflammasome could...