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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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 significantly mitigate CD8⁺CD69⁺CD103⁺ T_RM cell-mediated renal damage in LN.

CD8+ tissue-resident memory cells; IL-1β; Lupus nephritis; NLRP3 inflammasome.