NLRP3 inflammasome in cancer and metabolic diseases

Abstract

The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1β or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome-mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway.

Figure 1.. Mechanism of NLRP3 inflammasome activation.

The canonical NLRP3 inflammasome activation requires two steps. The priming step occurs when inflammatory stimuli are sensed by Toll-like receptors (TLRs), the interleukin-1 receptor (IL-1R), and the TNF receptor (TNFR). The activation step is provided by a wide range of stimuli including ATP, pore forming toxins, particulate matter, silica crystals, ion flux, etc. FADD and caspase-8 (CASP8) promote the transcription of NLRP3 and IL-1β. CASP8, FADD, transforming growth factor β-activated kinase 1 (TAK1), DDX3X, and NEK7 are all reported to regulate the activation of the NLRP3 inflammasome. Z-DNA-binding protein 1 (ZBP1)-dependent NLRP3 inflammasome activation occurs in response to influenza virus. Non-canonical NLRP3 inflammasome activation occurs in response to cytosolic lipopolysaccharide (LPS) and is dependent on CASP11, which is the mouse homolog of human CASP4 and CASP5. Activated CASP1 or CASP11 cleaves gasdermin D (GSDMD), which then forms pores in the plasma membrane causing cell lysis (pyroptosis). GSDMD pores also facilitate the release of the mature forms of IL-1β and IL-18.

Figure 2.. NLRP3 inflammasome in cancer.

(A) NLRP3 mediates the production of IL-18, which contributes to protection against colitis-associated colorectal cancer. IL-18 increases the tumoricidal activity of natural killer (NK) cells against metastasized colonic tumor cells in the mouse liver. IL-18 also downregulates IL-22BP which modulates colorectal cancer. NLRP3 also drives T-cell responses via IL-1β to inhibit transplantable tumor cells. (B) The NLRP3/IL-1β/IL-18 axis suppresses the tumoricidal activity of NK cells to promote methylcholanthrene (MCA)-induced fibrosarcoma. Overexpression of IL-1β mobilizes myeloid-derived suppressor cells (MDSCs) to the stomach and induces gastric cancer. In primary and metastatic mammary tumors, IL-1 signaling drives the accumulation of MDSCs and promotes the tumors. IL-1β also induces the secretion of IL-17 by CD4⁺ T cells and dampens the antitumor efficacy of chemotherapeutic agents in thyoma. Inflammasome-independent activity of NLRP3 suppresses NK cells and increases lung metastasis in certain models of melanoma^, .

Figure 3.. NLRP3 inflammasome in diabetes and obesity.

Obesity-related danger signals such as palmitate, lipids, and ceramides promote the activation of the NLRP3 inflammasome. Ceramides are generated from the endoplasmic reticulum and/or through the conversion of sphingomyelins located in the plasma membrane. Saturated fatty acids such as palmitate increase mitochondrial reactive oxygen species (mtROS) by reducing autophagy through the blockade of 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling. Elevated homocysteine levels can also activate the NLRP3 inflammasome through the induction of the hypoxia-inducible factor 1α (HIF1α)/phospholipase A2 group 16 (PLA2G16) axis by generating adipocyte-derived lysophosphatidyl choline (Lyso-PC). The release of IL-1β downstream of NLRP3 activation causes insulin resistance and reduces glucose uptake in insulin target tissues such as muscle, liver, and adipose tissues, leading to the pathogenesis of diabetes and obesity.

Figure 4.. NLRP3 inflammasome in atherosclerosis.

Calcium phosphate crystals and cholesterol crystals are taken into the lysosome by phagocytosis, or intracellular cholesterol crystals are formed when oxidized low-density lipoprotein (oxidized-LDL) is taken up by the scavenger receptor CD36. An excess of crystals in atherosclerosis causes lysosomal destabilization and rupture. Rupturing of lysosomes leads to the leakage of the lysosomal enzyme cathepsin B, resulting in NLRP3 inflammasome activation. The release of IL-1β downstream of NLRP3 activation signals to neighboring monocytes/macrophages, endothelial cells, and smooth muscle cells to promote the pathogenesis of atherosclerosis.