Pharmacological Modulation of NLRP3: From Therapy Personalization to Innovative Drugs

The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome is a multiprotein complex fundamental for the secretion of pro-inflammatory cytokines during the innate immune response. NLRP3 dysregulation is implicated in the pathogenesis of several diseases, such as inflammatory bowel disease, arthritis, cancer, Alzheimer's disease, and type 2 diabetes. The pharmacological modulation of NLRP3 by several compounds, which are fully described in this review, represents an important strategy to regulate inflammatory processes. Moreover, NLRP3 is also involved in drug-related adverse reactions, and its pharmacological modulation represents a rapid strategy to mitigate such adverse effects, as reported in this study. NLRP3 inflammasome activation is tightly regulated by post-transcriptional modifications and epigenetic factors, such as long non-coding RNAs (lncRNAs) and DNA methylation, as well as other interacting regulators. Recently, different studies have revealed the importance of NLRP3 levels in predicting drug response. In particular, the methylation of the NLRP3 promoter, which is associated with the inflammasome expression level, emerged as a new promising pharmacoepigenetic biomarker for the glucocorticoid therapy response in several inflammatory disease conditions.