Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8CD69CD103 T cells.

BACKGROUND

Renal CD8 tissue-resident memory T (T) 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 cells in LN.

METHODS

NLRP3 inflammasome activity in renal CD8 T cells from lupus-prone MRL/lpr mice and in vitro induced human CD8CD103 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 cells in LN.

RESULTS

Activation of the NLRP3 inflammasome was confirmed in renal CD8CD69CD103 T cells derived from mice with LN and in vitro-induced human CD8CD103 T-like cells. MCC950 curtailed the infiltration and activity of CD8CD69CD103 T cells and enhanced renal outcomes. MCC950 also suppressed the maturation and functional capabilities of CD8CD103 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 CD8CD69CD103 T cells contributes to LN pathogenesis by regulating cell differentiation and effector functions. Therapeutically targeting the NLRP3 inflammasome could significantly mitigate CD8CD69CD103 T cell-mediated renal damage in LN.