The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

Abstract

In response to inflammatory stimuli, immune cells reconfigure their metabolism and bioenergetics to generate energy and substrates for cell survival and to launch immune effector functions. As a critical component of the innate immune system, the nucleotide-binding and oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome can be activated by various endogenous and exogenous danger signals. Activation of this cytosolic multiprotein complex triggers the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and initiates pyroptosis, an inflammatory form of programmed cell death. The NLRP3 inflammasome fuels both chronic and acute inflammatory conditions and is critical in the emergence of inflammaging. Recent advances have highlighted that various metabolic pathways converge as potent regulators of the NLRP3 inflammasome. This review focuses on our current understanding of the metabolic regulation of the NLRP3 inflammasome activation, and the contribution of the NLRP3 inflammasome to inflammaging.

Elamipretide (SS-31) Improves Functional Connectivity in Hippocampus and Other Related Regions Following Prolonged Neuroinflammation Induced by Lipopolysaccharide in Aged Rats

“…Another study based on single dose of LPS injection (2 mg/kg) reported that the neuronal function followed by systemic inflammation is NLRP3 inflammasome dependent (14 days after injection) in which the spine density of basal cell in the hippocampus CA1 region still remains significantly decreased even 3 months after the LPS exposure (Beyer et al, 2020 ). Meanwhile, a great number of evidence has shown that the NLRP3 inflammasome activation also contributes to aging process (Meyers and Zhu, 2020 ), which also supports our result that the inflammatory responses in the aged rat hippocampus may be long-lasting even the LPS and SS-31 no longer exist. Although we did not measure the level of NLRP3 inflammasome, we used the same doses and administration method of LPS.…”

Integrative medicine considerations for convalescence from mild-to-moderate COVID-19 disease

“…Various nutrient components of an anti-inflammatory diet, such as monosaturated and polyunsaturated fatty acids 25 and plant-derived flavonoids 26 are associated with decreased activation of the NLRP3 inflammasome. The NLRP3 inflammasome is a critical cytosolic protein complex responsible for both acute and chronic inflammation in response to various pathogens 27 , including SARS-CoV-2. 28 , 29 Anti-inflammatory diets are associated with improved pulmonary function in non-asthmatic Hispanic adults 30 and improved lung function and lower mortality in individuals with COPD.…”

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

“…Crystals-induced lysosomal destabilization (following engulfment of cholesterol, MSU, βamyloid) that leads to the cytosolic release of cathepsins and Ca 2+ results in NLRP3 inflammasome activation (36,37). Also ROS production following ER stress due to the accumulation of unfolded proteins (38); changes in metabolites and enzymes related to mitochondria function (succinate, itaconate, ATP) (39) or mitochondrial dysfunction (mtROS, oxidized mtDNA, cardiolipin) are proved to be inducers of NLRP3 activation (40). Importantly, mitochondria-associated membranes (MAMs) serve as platform for the NLRP3 inflammasome assembly (36,41,42).…”

“…Expression of CD36 scavenger receptor, that transports cholesterol containing oxLDL to MFs, are regulated by PPARγ (75), while that of the ABCA1/ABCG1, that mediates cholesterol efflux, is regulated by LXR (76, 77). The detailed mechanism of their actions on NLRP3 inflammasome has recently been described in excellent reviews (39,(78)(79)(80). In the following section, we highlight known regulatory roles and mechanisms that nuclear receptors exert on NLRP3 inflammasome ( Table 1).…”