Molecular Mechanism of NLRP3 Inflammasome in Inflammatory Diseases and Tumors

Abstract

The nucleotide-binding and oligomerization domain-like receptors (NLRs) are pattern recognition receptors. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), a member of the NLRs family, can form a protein complex with caspase-1, apoptosis-associated speck-like protein and caspase recruitment domain. And its assembly and activation cause inflammatory reaction and are closely related to the effects of antitumor immunity. The activation of NLRP3 inflammasome can induce polarization, hyperactivity or pyroptosis of immune cells, releasing interleukin-1β (IL-1β) and interleukin-18, which leads a cascade immunity or inflammatory responses. As an important component of the innate immune system, the NLRP3 inflammasome plays vital roles inflammatory diseases and tumors. In this review, we attempt to summarize the recent findings about the role of NLRP3 in the pathogenesis of tumors and inflammatory diseases such as diabetes, Alzheimer disease, and atherosclerosis.

Keywords: NLRP3 inflammasome; inflammatory diseases; metabolism disease; tumors.

Figure 1

Mechanism of NLRP3 inflammasome activation. Classical NLRP3 inflammasome activation involves two steps. The priming step occurs when inflammatory stimuli are sensed by TLRs, IL‐1Rs and TNFRs to upgrade NLRP3. The activation signal is provided by a wide range of stimuli, including ATP, RNA virus, ion flux AND mitochondrial dysfunction, ROS promote NLRP3 inflammasome activation to release mature IL‐1β, IL‐18 and caspase‐1.

Figure 2

NLRP3 inflammasome in inflammatory disease. LDL, CCS are all reported to regulate activation of the NLRP3 inflammasome and downstream release of IL‐1β leads to insulin resistance, Aβ accumulation in brain and Inflammation of arteries. NLRP3 inflammasome binds to TXNIP to target pancreatic β‐cell apoptosis and inhibit glucose recruitment in peripheral blood, leading to the pathogenesis of diabetes and obesity.

Figure 3

(A) The P53 mutation‐induced WNT signaling pathway mediates the NLRP 3‐IL‐1 β axis in TAMs to promote systemic inflammation and tumor metastasis in the whole body. In primary and metastatic breast tumors, the NLRP3 inflammasome suppresses NK cell activity, releases GSDMD n‐terminal fragments, promoting the maturation and secretion of cytokines IL‐18 and IL‐1 β to, leading to pyroptosis. Overexpressed IL‐1 signaling pathway drives the accumulation of MDSCs and promotes tumors. IL‐1 β also inhibited the antitumor efficacy of the chemotherapeutic agent 5‐FU in CRC. (B) NLRP 3 mediates IL‐18 production and increases NK cell tumoricidal activity, which inhibits metastatic able CA‐CRC tumor cells. NLRP 3 also exhibits a tumoricidal activity against metastatic colon tumor cells in the mouse liver by driving T cell responses via IL‐1β.