Glycolysis - a key player in the inflammatory response

Abstract

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.

Keywords: ageing; immune cells; immunometabolism; inflammation; metabolites.

Fig. 1

Distinctive metabolic profile of cells during the inflammatory response. Inflammatory cells such as Th1 and Th17 cells, activated microglia, endothelial cells or M1‐type macrophages are known to rely mainly on glycolysis and glutaminolysis upon inflammation, displaying a dysregulated TCA cycle and increased rate of lipid synthesis and the PPP to meet the highly biosynthetic and bioenergetic demand. Once the inflammatory response is completed, regulatory and memory T cells, resting microglia and M2‐type macrophages, which depend mostly on OXPHOS and fatty acid oxidation, are involved in the maintenance of the tissue homoeostasis to dampen the response.

Fig. 2

Molecular mechanisms dictating the metabolic control of the inflammatory phenotype. The metabolic signature of inflammatory cells fuels their pro‐inflammatory phenotype through different molecular mechanisms: (A) intracellular signalling events. For example, the PEP produced during glycolysis inhibits the ER calcium channel SERCA. The cytosolic calcium concentration is then increased, activating NFAT, which drives the expression of pro‐inflammatory genes. (B) Sophisticated post‐transcriptional modifications. Some glycolytic enzymes have a dual role and can act as RNA binding proteins. For example, GAPDH interacts with Ifng mRNA blocking its translation. When the glycolytic demand is high, GAPDH is required for glycolysis and the Ifng mRNA is released and translated, increasing the IFN‐γ secretion. (C) Post‐translational modifications. Certain metabolites can post‐translationally modify proteins. For example, succinate is accumulated in the cytosol of activated cells, resulting in the addition of succinyl groups to the glycolytic enzyme PKM2, which loses its tetrameric conformation. The hypersuccinylated dimeric PKM2 enters the nucleus and complex with HIF‐1α, enhancing the expression of the pro‐inflammatory cytokine IL‐1β. (D) Changes in the epigenome. The function of epigenetic remodelers is tightly modulated by the levels of certain metabolites. For example, upon activation, the intracellular levels of acetyl‐CoA are increased. The acetyl‐CoA is then used to acetylate histones enhancing the expression of pro‐inflammatory cytokines. GAP, glyceraldehyde 3‐phosphate; Pyr, pyruvate.

Fig. 3

Glycolysis orchestrates the behaviour of inflammatory cells. Upon inflammation, immune cells are reprogrammed towards glycolysis, enhancing this pathway at the expense of OXPHOS and, in macrophages, disbalancing the TCA cycle. As a consequence, glycolysis and broken TCA cycle‐released metabolites such as lactate, citrate or succinate accumulate in immune cells promoting signalling, post‐translational and epigenetic modifications which drive the inflammatory response. Moreover, glycolytic intermediates fuel other pathways such as the PPP, which provides biosynthetic molecules, and the hexosamine one, which generates UDP‐GlcNAc for glycation reactions. Citr, citrate; Fum, fumarate; Gln, glutamine; Itac, itaconate; Lact, lactate; Pyr, pyruvate; Succ, succinate.