The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome

Abstract

Sterile inflammation is a cornerstone of immune activation in obesity and type 2 Diabetes Mellitus. The molecular underpinnings of this inflammation include nutrient excess-mediated activation of the innate immune NLRP3 inflammasome. At the same time, disruption of mitochondrial integrity is emerging as an integral control node in NLRP3 inflammasome activation and is also associated with caloric overload conditions including obesity and diabetes. Conversely, caloric restriction and fasting mimetic interventions alleviate these caloric excess-linked diseases and reduce inflammation and the NLRP3 inflammasome. The objective of this review is to integrate the findings linking mitochondrial integrity to the activation of the NLRP3 inflammasome and to evaluate how caloric restriction or caloric restriction mimetic compounds may play a role in attenuating the NLRP3 inflammasome and sterile inflammation.

Keywords: Mitochondria; NLRP3 inflammasome; Obesity; Sirtuins; Sterile inflammation.

Figures

Fig. 1

Nutrients linked to NLRP3 inflammasome activation. Schematic showing the effects of different nutrients on the NLRP3 inflammasome. Here, excess levels of nutrients associated with caloric overload including glucose and fatty acids and reactive lipids including, e.g., ceramide play a role in activating the NLRP3 inflammasome. Low-level circulatory endotoxemia (LPS), which is also evident in obesity, could also function to activate the NLRP3 inflammasome. In contrast, nutrient deprivation such as caloric restriction or fasting via the increase in NAD+ may also blunt the inflammasome. The mechanisms here have not been fully elucidated but appear to function in part through augmenting mitochondrial fidelity. The ketone body, β-hydroxybutyrate suppresses the inflammasome via the prevention of K+ efflux and by preventing oligomerization of ASC

Fig. 2

Schematic of NLRP3 inflammasome activation. NLRP3 priming usually results from activation of Toll-like receptor (TLR)-mediated activation of NF-κB, which then transactivates canonical NLRP3 complex components and associated cytokine pre-proteins including those encoding for IL-1β and IL-18. Subsequent pathogenor molecular damage-associated patterns, through either the promotion of K+ efflux, or the disruption of intracellular organelles (with the subsequent generation of, e.g., mitochondrial ROS, ER stress or lysosomal accumulation of crystals) promotes oligomerization of NLRP3 supercomplexes. These trigger collectively function as pathogen- or disease-associated molecular patterns (PAMPS/ DAMPS). This results in the activation of caspase-1, which cleaves pro-IL-1β and Pro-IL-18 to generate cytokines which initiate subsequent immune amplification. ASC apoptosis-associated Speck-like protein containing a caspase-recruitment domain, NLRP3 Nod-like receptor family protein 3

Fig. 3

The role of mitochondria in NLRP3 inflammasome assembly and activation. The disruption of mitochondria can promote inflammasome assembly and activation through the release of ROS signaling and/or by the extrusion of cardiolipin (CL) or mitochondrial DNA (mtDNA) into the cytoplasm. Emerging data also support that mitochondria may function as a platform for the enucleation and oligomerization of inflammasome regulatory protein components to enable the activation of caspase-1. Not shown is the mitochondria-associated viral signaling (MAVS), which may function as the anchor to tether the inflammasome multiprotein complex to the mitochondria

Fig. 4

The caloric load-dependent role of sirtuins in the control of the NLRP3 inflammasome. Under conditions of caloric sufficiency, the relative NAD+ levels are reduced with diminished sirtuin activity in the nucleus (SIRT1 and 6), cytoplasm (SIRT2) and the mitochondria (SIRT3). The resultant acetylation of canonical sirtuin targets predisposes to upregulation of inflammasome encoding genes, generation of ROS and oxidized mitochondrial DNA (Ox mtDNA) in the mitochondria, and in the spatial trafficking of mitochondria towards the endoplasmic reticulum (ER) platform to trigger NLRP3 assembly. Conversely, with caloric restriction, the NAD+ levels are higher, with sirtuin activation and chromatin and protein deacetylation, resulting in counter-regulatory controlling events to blunt the NLRP3 inflammasome