Immunometabolic control of trained immunity

Abstract

Innate immune cells can adopt long-term inflammatory phenotypes following brief encounters with exogenous (microbial) or endogenous stimuli. This phenomenon is named trained immunity and can improve host defense against (recurrent) infections. In contrast, trained immunity can also be maladaptive in the context of chronic inflammatory disorders, such as atherosclerosis. Key to future therapeutic exploitation of this mechanism is thorough knowledge of the mechanisms driving trained immunity, which can be used as pharmacological targets. These mechanisms include profound changes in intracellular metabolism, which are closely intertwined with epigenetic reprogramming at the level of histone modifications. Glycolysis, glutamine replenishment of the tricarboxylic acid cycle with accumulation of fumarate, and the mevalonate pathway have all been identified as critical pathways for trained immunity in monocytes and macrophages. In this review, we provide a state-of-the-art overview of how these metabolic pathways interact with epigenetic programs to develop trained immunity.

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

“…Accumulation of succinate and fumarate leads to the inhibition of DNA demethylases and lysine demethylases (KDMs) via product inhibition. Accordingly, fumarate accumulation (e.g., derived from glutaminolysis) was shown to inhibit KDM5 histone demethylases, altering histone H3 at lysine 4 (H3K4) methylation at the promoters of pro-inflammatory cytokines, such as Tnfa and Il6 [ 33 , 85 , 86 , 161 , 167 , 192 , 193 , 194 , 195 , 196 ] and regulating the chromatin-modifying activities of histone acetyltransferases or deacetylases by altering their post-translational lysine methylation status [ 194 ]. Fumarate induces epigenetic changes in macrophages that are associated with trained immunity [ 86 , 193 ].…”

“…This was accompanied by an enrichment of H3K4me3 on the promoters of the cytokine genes, due to a direct inhibitory effect of fumarate on the KDM5 family of histone demethylases, which are responsible for demethylation of H3K4 [ 86 , 194 , 197 ]. This effect could partly be restored by the addition of α-ketoglutarate [ 194 , 195 , 196 , 197 ]. The striking elevation of succinate and fumarate induced by the metabolic rewiring of trained macrophages, therefore, represents a plausible mechanism underlying the integration of immunometabolic and epigenetic programs in trained immunity [ 82 , 194 ].…”

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

“…Activation of immune cells leads to the remodeling of the TCA cycle via a process called the 'immunologic Warburg effect'. The TCA cycle intermediates citrate, α-ketoglutarate, succinate, and fumarate regulate inflammatory gene expression [26,33,79,80,156,162,[187][188][189][190][191]. Innate immune cells use ROS as a key signaling and functional molecule during inflammation.…”

“…Accumulation of succinate and fumarate leads to the inhibition of DNA demethylases and KDMs via product inhibition. Accordingly, fumarate accumulation (e.g., derived from glutaminolysis) was shown to inhibit KDM5 histone demethylases, altering H3K4 methylation at the promoters of pro-inflammatory cytokines, such as Tnfa and Il6 [33,79,80,156,162,[187][188][189][190][191] and regulating the chromatin-modifying activities of histone acetyltransferases or deacetylases by altering their post-translational lysine methylation status [189]. Fumarate induces epigenetic changes in macrophages that are associated with trained immunity [80,188].…”

“…This was accompanied by an enrichment of H3K4me3 on the promoters of the cytokine genes, due to a direct inhibitory effect of fumarate on the KDM5 family of histone demethylases, which are responsible for demethylation of H3K4 [80,189,192]. This effect could partly be restored by the addition of α-ketoglutarate [189][190][191][192]. The striking elevation of succinate and fumarate induced by the metabolic rewiring of trained macrophages, therefore, represents a plausible mechanism underlying the integration of immunometabolic and epigenetic programs in trained immunity [76,189].…”