Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 inflammasome: From action mechanism to therapeutic target in clinical trials.

Abstract

The nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a critical modulator in inflammatory disease. Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome, Muckle-Wells syndrome, and familial cold autoinflammatory syndrome 1. To date, a great effort has been made to decode the underlying mechanisms of NLRP3 activation. The priming and activation of NLRP3 drive the maturation and release of active interleukin (IL)-18 and IL-1β to cause inflammation and pyroptosis, which can significantly trigger many diseases including inflammatory diseases, immune disorders, metabolic diseases, and neurodegenerative diseases. The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials. Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields. In this minireview, we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways. We then reviewed the molecular and cellular pathways of NLRP3 in many diseases, including obesity, diabetes, and other metabolic diseases. In addition, we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy. Finally, clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.