Structural dynamics, pathogenic mechanisms, and therapeutic targeting of the NLRP3 inflammasome in lupus nephritis

Abstract

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a central role in the pathogenesis of LN. Aberrant activation of the NLRP3 inflammasome directly promotes glomerular injury, proteinuria, and tubulointerstitial fibrosis through the induction of pyroptosis and the release of interleukin-1β (IL-1β) and IL-18. The expression level of the NLRP3 inflammasome is positively correlated with disease activity, making it both a key driver of acute renal injury in LN and a promising therapeutic target. In this review, a comprehensive summary of the structural features of NLRP3 is provided, including the pyrin domain (PYD), the nucleotide-binding oligomerization domain (NACHT), and the leucine-rich repeat domain (LRR). Additionally, the interaction between NIMA-related kinase 7 (NEK7) and the LRR domain is characterized, as well as the role of the fish-specific NACHT-associated (FISNA) domain in oligomerization. The canonical and non-canonical activation signaling pathways of the NLRP3 inflammasome are thoroughly analyzed. The pathological roles of the NLRP3 inflammasome in kidney-resident cells, including podocytes and renal tubular epithelial cells, as well as infiltrating immune cells, such as macrophages and T cells, are comprehensively discussed. Its crosstalk with multiple signaling pathways is also examined. Finally, the therapeutic potential of various intervention strategies, including direct inhibitors targeting NLRP3, upstream signaling pathway modulators, natural compounds, and novel gas therapies, in preclinical models of LN is evaluated. This review provides a comprehensive overview of the role of the NLRP3 inflammasome in LN and offers a theoretical basis for the development of novel NLRP3-targeted therapeutic strategies.