Glycolysis in Innate Immune Cells Contributes to Autoimmunity

Abstract

Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine-threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.

Keywords: autoimmune diseases; glycolysis; immunometabolism; innate immune cells; therapeutic target.

Figure 1

Simplified flowchart of glycolysis. Glucose entering cells is metabolized by HK to G6P, which provides a substrate for PPP. PPP generates ribose 5-phosphate and abundant NADPH. Those NADPH-dependent hydroxylases are manipulated by PPP activity, such as K3H. G6P undergoes a series of oxidative decompositions to generate 3-phosphoglycerate, providing raw materials for serine/glycine biosynthesis. PKM2 controls the final step of glycolysis and generates pyruvate. The produced pyruvate is used mainly in OXPHOS and the tricarboxylic acid TCA cycle to generate more ATP. Monocarboxylate transporter 4, MCT4; Lactic dehydrogenase A, LDHA; Phosphofructokinase-1, PFK-1; Fructose-2,6-bisphosphate, F2,6BP; Kynurenine 3-hydroxylase, K3H.

Figure 2

Schematic illustration of glycolysis regulating innate immune cell function. Glycolysis is the main energy production pathway for neutrophils. Impairing glycolysis and PPP can destroy neutrophil function, including chemotaxis and ROS production, even phagocytosis. NETs formation is dependent on adequate glucose flux, G6P, NOX2, and NAD⁺/NADPH. The TLR/AMPK/mTORC1 regulates glycolysis-dependent antimicrobial activity in monocytes. TLR/AMPK/mTORC1 axis is also responsible for M1-type macrophage induction, expression of glycolytic enzymes (GLUT1 and PKM2) in these cells and their IL-12 secretion. Solute carrier family 15 member A4 (SLC15A4) is likely to maintain the interaction of AMPK and mTORC1 by acting as a scaffold. PKM2 in M1 macrophages contributes to IL-1β transcription via STAT3 signaling. Both enhanced PPP and IDO-1 in M1 macrophages facilitate kynurenine accumulation, stimulating mTORC1 activity in T cells. Akt/mTORC1-mediated glycolysis also affects M2-like macrophage differentiation and gene profile expression (Arg1, Cdh1, YM-1, Mrc1, and resistin-like β) when OXPHOS in macrophages is inhibited. The interferon regulatory factor 4 (IRF4), which is downstream of the IL-4 receptor α/STAT6 and colony-stimulating factor 1 receptor (CSF1R)/mTORC2 signaling axis, promotes glycolysis (enhanced expression of LDHA, GAPDH and HK2) during M2 activation. DCs activated by TLRs depend on glycolysis flux to fulfill metabolic and functional requirements, including secretion of TNF-α, IL-6 and IL-12. TBK1/Ikkϵ-mediated Akt phosphorylation responds to lipopolysaccharide stimulation of TLRs on DCs. p-Akt/mTORC1 immediately promotes the transcription of HK2 and LDHA via HIF-1α. Cxc chemokine receptor 7 (CCR7)-mediated HIF-1α induction contributes to DC migration.