Immunometabolism of Macrophages in Bacterial Infections

Abstract

Macrophages are important effectors of tissue homeostasis, inflammation and host defense. They are equipped with an arsenal of pattern recognition receptors (PRRs) necessary to sense microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit rapid energetically costly innate immunity responses to protect the organism. The interaction between cellular metabolism and macrophage innate immunity is however not limited to answering the cell's energy demands. Mounting evidence now indicate that in response to bacterial sensing, macrophages undergo metabolic adaptations that contribute to the induction of innate immunity signaling and/or macrophage polarization. In particular, intermediates of the glycolysis pathway, the Tricarboxylic Acid (TCA) cycle, mitochondrial respiration, amino acid and lipid metabolism directly interact with and modulate macrophage effectors at the epigenetic, transcriptional and post-translational levels. Interestingly, some intracellular bacterial pathogens usurp macrophage metabolic pathways to attenuate anti-bacterial defenses. In this review, we highlight recent evidence describing such host-bacterial immunometabolic interactions.

Keywords: bacteria; immunometabolism; infection; inflammation; innate immunity.

Figure 1

Macrophage innate immunity effectors. (A) Macrophage polarization to M1 or M2 is an over-simplified in vitro model that does not illustrate the complexity of macrophage ontogeny and phenotypes observed in vivo. The main macrophage receptors, transcription factors and markers associated with the M1/inflammatory and bactericidal (red) versus M2/wound healing (green) phenotypes are shown. M1 macrophages shift their metabolism to aerobic glycolysis while M2 macrophages have increased mitochondrial OXPHOS and lipid metabolism. (B) Trained immunity in myeloid cells. The graph depicts the enhanced innate immunity response induced upon rechallenge with the same or other microorganisms. Such innate memory is mediated by metabolites (mevalonate, acetyl-coA, NAD, α-KG, fumarate) and metabolic effectors (AKT, mTOR, HIF-1α) that converge on epigenetic (H3K4me3, H3K27ac) reprogramming of myeloid progenitors (Netea et al., 2020).

Figure 2

Metabolic adaptations in activated macrophages. (A) Inflammatory macrophages are characterized by NO∙ -mediated inhibition of glucose flux in the Tricarboxylic Acid (TCA) cycle. NO∙ inhibits pyruvate dehydrogenase (PDH), aconitase 2 (ACO2), and SDH presumably through cysteine nitrosylation. This results in citrate accumulation and its conversion to itaconate which also blocks SDH. Citrate conversion to acetyl coA by ATP citrate lyase in the cytosol leads to histone acetylation and activation of inflammatory gene loci. SDH inhibition results in succinate accumulation, which inhibits PHDs, stabilizing HIF-1α and enhancing its transcriptional induction of glycolytic and inflammatory genes (e.g. pro-IL-1b). Succinylation of PKM2 leads to its inhibition and translocation to the nucleus where it promotes HIF-1α activity. RET mediated by succinate accumulation leads to ROS production. (B) Metabolic adaptations in M2 macrophages are represented in green. Macrophage tolerance in response to prolonged LPS exposure are in yellow.

Figure 3

Bacterial strategies targeting macrophage metabolism toward a successful infection. Bacteria manipulate metabolic pathways to enhance the necessary nutrient resources required for their survival, including glucose and lactate as carbon sources. The antibacterial effects of itaconate is countered by some bacteria through expression of itaconate degradative enzymes. Bacteria can “hide” from innate sensors by altering host metabolic enzymes (e.g. PDE2 conversion into lipoyl-E2-PDH that blocks TLR1/2 stimulation by bacterial lipopeptides). Chronic infection by intracellular bacteria is promoted through the actions of PPARδ and PPARγ that promote a wound healing phenotype and enhance glucose availability for the bacteria.