Abstract
Cytoplasmic nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) forms an inflammasome with apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1, which is followed by the cleavage of pro-caspase-1 to active caspase-1 and ultimately the activation of IL-1β and IL-18 and induction of pyroptosis in immune cells. NLRP3 activation in kidney diseases aggravates inflammation and subsequent fibrosis, and this effect is abrogated by genetic or pharmacologic deletion of NLRP3. Inflammasome-dependent NLRP3 mediates the progression of kidney diseases by escalating the inflammatory response in immune cells and the cross-talk between immune cells and renal nonimmune cells. However, recent studies have suggested that NLRP3 has several inflammasome-independent functions in the kidney. Inflammasome-independent NLRP3 regulates apoptosis in tubular epithelial cells by interacting with mitochondria and mediating mitochondrial reactive oxygen species production and mitophagy. This review will summarize the mechanisms by which NLRP3 functions in the kidney in both inflammasome-dependent and inflammasome-independent ways and the role of NLRP3 and NLRP3 inhibitors in kidney diseases.
Highlights
Inflammation is a defense system against pathogens in the host, and it can prevent pathogens from invading and spreading through disrupted barriers [1]
nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) deficiency in immune cells contributes to decreasing renal ischemic renal injury (IRI) in part, NLRP3 inhibition in renal tubular epithelial cells (TECs) could be the main factor in improving the initial renal tubular damage in an inflammasome-independent manner
It is under debate whether tubular IL-18 originated from an inflammasome-dependent way [85,86]. These findings indicate that inflammasome-dependent NLRP3 in immune cells and podocytes is important for lupus nephritis progression
Summary
Inflammation is a defense system against pathogens in the host, and it can prevent pathogens from invading and spreading through disrupted barriers [1]. Recent studies showed that sterile damage-associated molecular patterns (DAMPs) could trigger inflammation via pattern recognition receptors (PRRs), such as nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), RIG-like receptors, and Toll-like receptors (TLRs), and induce the production of inflammatory cytokines and chemokines [4,5]. Blockade of IL-1β, the end product of the activated NLRP3 inflammasome, failed to mitigate kidney disease, whereupon interest concerning inflammasome-independent NLRP3 increased [11,12,13]. The process by which NLRP3 contributes to kidney injury and disease progression is assumed to encompass a combination of inflammasome-dependent and inflammasome-independent pathways [7,11]. We will address what has been studied so far about the role of NLRP3, primarily focusing on the mechanism of action of the inflammasome-independent and inflammasome-dependent forms of NLRP3 in kidney diseases
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