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

Renal CD8+ tissue-resident memory T (TRM) 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 TRM cells in LN. NLRP3 inflammasome activity in renal CD8+ TRM 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+ TRM cells in LN. Activation of the NLRP3 inflammasome was confirmed in renal CD8+CD69+CD103+ TRM cells derived from mice with LN and in vitro-induced human CD8+CD103+ TRM-like cells. MCC950 curtailed the infiltration and activity of CD8+CD69+CD103+ TRM 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+ TRM cells contributes to LN pathogenesis by regulating cell differentiation and effector functions. Therapeutically targeting the NLRP3 inflammasome could significantly mitigate CD8+CD69+CD103+ TRM cell-mediated renal damage in LN.