Multifactorial functions of the inflammasome component NLRP3 in pathogenesis of chronic kidney diseases

The NLRP3 inflammasome is a cytosolic multiprotein caspase-activating complex platform involved in innate immunity required for the maturation and release of interleukin (IL)-1β and IL-18. Both cytokines activate their respective receptors present on cells inside and outside kidneys, resulting in the release of other proinflammatory cytokines to set up an inflammatory milieu both within the kidney and systemically. The canonical NLRP3-ASC-caspase-1-IL-1β-IL-18 axis has been shown to contribute to the pathophysiology of several kidney diseases by regulating renal necroinflammation. However, many recent studies have emphasized the inflammasome-independent functions of NLRP3 in chronic kidney disease (CKD) pathogenesis. This review highlights the contribution of the inflammasome-independent functions of NLPR3, for example, in fibrotic tissue remodeling, in tubular epithelial cell apoptosis, and in metabolic pathways, during the development and progression of CKD in various experimental models and humans. Interestingly, therapies targeting the inflammasome effectors (e.g., IL-1 receptor antagonists and IL-1β) have been approved for therapeutic use for NLRP3-dependent diseases; however, no NLRP3 antagonists have been approved for therapeutic use until now. This review highlights the double-edged sword-like functions of NLRP3 in the regulation of renal necroinflammation and fibrosis and therefore emphasizes the urgent need for specific NLRP3 inhibitors because of the broad therapeutic potential they offer for the treatment of CKD.