How metabolism generates signals during innate immunity and inflammation

Abstract

The interplay between immunity, inflammation, and metabolic changes is a growing field of research. Toll-like receptors and NOD-like receptors are families of innate immune receptors, and their role in the human immune response is well documented. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as type 2 diabetes and atherosclerosis. The proinflammatory cytokine IL-1β appears to play a central role in these disorders. There is also evidence that metabolites such as NAD(+) (acting via deacetylases such as SIRT1 and SIRT2) and succinate (which regulates hypoxia-inducible factor 1α) are signals that regulate innate immunity. In addition, the extracellular overproduction of metabolites such as uric acid and cholesterol crystals acts as a signal sensed by NLRP3, leading to the production of IL-1β. These observations cast new light on the role of metabolism during host defense and inflammation.

Keywords: Inflammation; Innate Immunity; Metabolic Diseases; Metabolic Regulation; Metabolism; Signal Transduction.

Figures

FIGURE 1.

Succinate is a signal generated in response to activation of TLR4 by LPS, leading to HIF1α activation. Activation of TLR4 by LPS leads to a profound change in metabolism, including increased glycolysis and the pentose phosphate pathway (not shown). In addition, LPS alters the TCA cycle such that there is an increase in succinate. This occurs via the alteration in glutamine metabolism via both anaplerosis to α-KG and the GABA shunt. Succinate then inhibits PHDs, increasing HIF1α and promoting the expression of IL-1β and other genes. The increase in succinate may also promote protein succinylation, the consequences of which are not yet known.

FIGURE 2.

NAD+, AMPK, and SIRT1 as key inflammatory regulators. Agents such as nigericin, ATP, and uric acid crystals lead to mitochondrial damage, which in turn leads to a decrease in NAD+. This limits SIRT2 activity, allowing acetylation of tubulin to persist, which in turn enhances NLRP3 activity by promoting the trafficking of NLRP3 to the mitochondria, enhancing its activation. Because these agents are all NLRP3 activators, this could create a positive feedback loop sustaining NLRP3 activation, leading to IL-1β production. Caloric restriction has the opposite effect and leads to an increase in NAD+. This leads to the activation of SIRT1, a deacetylase that will promote mitochondrial biogenesis and function via PGC-1β and inhibit NF-κB via deacetylation of the p65 subunit. Both of these events will have a net anti-inflammatory effect, with the promotion of mitochondrial function, also inhibiting NLRP3 activation. The increase in oxidative phosphorylation (which appears to be anti-inflammatory probably via an increase in NAD+) will restore the energy balance. Caloric restriction will also activate AMPK, which can also promote mitochondrial biogenesis. There is evidence for cross-talk between SIRT1 and AMPK. Finally, several anti-inflammatory agents, notably methotrexate and salicylate, have been shown to activate AMPK, as has the anti-T2D agent metformin. Metformin may mediate its effects in T2D via this process because limiting inflammation in this way could restore insulin sensitivity. MSU, monosodium urate.