Insulin Signaling and Insulin Resistance Facilitate Trained Immunity in Macrophages Through Metabolic and Epigenetic Changes

Abstract

Adaptation of the innate immune system has been recently acknowledged, explaining sustained changes of innate immune responses. Such adaptation is termed trained immunity. Trained immunity is initiated by extracellular signals that trigger a cascade of events affecting cell metabolism and mediating chromatin changes on genes that control innate immune responses. Factors demonstrated to facilitate trained immunity are pathogenic signals (fungi, bacteria, viruses) as well non-pathogenic signals such as insulin, cytokines, adipokines or hormones. These signals initiate intracellular signaling cascades that include AKT kinases and mTOR as well as histone methylases and demethylases, resulting in metabolic changes and histone modifications. In the context of insulin resistance, AKT signaling is affected resulting in sustained activation of mTORC1 and enhanced glycolysis. In macrophages elevated glycolysis readily impacts responses to pathogens (bacteria, fungi) or danger signals (TLR-driven signals of tissue damage), partly explaining insulin resistance-related pathologies. Thus, macrophages lacking insulin signaling exhibit reduced responses to pathogens and altered metabolism, suggesting that insulin resistance is a state of trained immunity. Evidence from Insulin Receptor as well as IGF1Receptor deficient macrophages support the contribution of insulin signaling in macrophage responses. In addition, clinical evidence highlights altered macrophage responses to pathogens or metabolic products in patients with systemic insulin resistance, being in concert with cell culture and animal model studies. Herein, we review the current knowledge that supports the impact of insulin signaling and other insulin resistance related signals as modulators of trained immunity.

Keywords: Akt; epigenetic; mTOR; macrophages; metabolism; trained immunity.

Figure 1

Crosstalk of TLR and Insulin signals. TLR triggering initiates a cascade of events that results in activation of NFkB and AKT leading to pro- and anti- inflammatory gene expression as well as genes regulating metabolism. Insulin signals also activate AKT and result in regulation of metabolic gene expression and at the same time crosstalk with TLR signaling.

Figure 2

Obesity and insulin resistance promote macrophage training. Macrophages chronically exposed to high levels of insulin as well as SFAs, adipokines, inflammatory cytokines, and low levels of endotoxin, all associated with obesity, obtain changes in Akt signaling, cell metabolism and epigenetic alterations in inflammatory genes that result in altered responses, described as innate immune training.