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.

The causes and consequences of trained immunity in myeloid cells

“…Since activated host cells consume more glucose than resting cells, glycolysis is activated during training/stimulation of the innate immune cells to meet the energy demand to serve a proinflammatory role ( 93 ). Although glycolysis is not an efficient way for the cell to generate ATP, this process can rapidly be induced upon stimulation of the innate immune cells ( 94 ). The primary function of the glycolysis cycle is to break glucose molecules to produce ATP and release pyruvate, which is further transformed into acetyl CoA and participates either in the TCA or fatty acid oxidation (FAO) cycle.…”

“…The persistent activation of glycolysis is regulated by a key transcriptional regulator, namely the hypoxia-inducible factor-1 alpha (HIF1α), which is stabilized by succinate, an intermediate metabolite of glycolysis. Furthermore, succinate and fumarate can act as epigenetic modulators for antagonizing histone or DNA methylation and facilitating long-lasting expression of genes involved in the glycolysis pathway ( 94 , 95 ). The increased glycolysis impacts the mammalian target of rapamycin (mTOR) and HIF-1α pathway representing the metabolic basis of trained immunity ( 96 ).…”

“…It has been reported that β-glucan can induce OXPHOS shift, resulting in a higher intracellular ratio of NAD + to its reduced form NADH, thus producing more ATP ( 97 , 101 , 102 ). However, recent findings suggest that trained innate immune cells can activate both glycolysis and OXPHOS pathways at the same time ( 94 ) to serve as cellular energy sources to meet the demands of activated/trained cells ( 103 ). In a study by Arts et al., the stimulation of macrophages with β-glucan and BCG upregulated the expression of glycolytic enzymes with an increase in NAD + and NADH ratio ( 104 ).…”

Insights into the pathogenic role of neutrophils in systemic lupus erythematosus

“…As elevated autoantibodies and deposition of immune complexes are the main characteristics of SLE patients, most pathological studies conducted on SLE so far have focused on abnormalities of the adaptive immune response [6 ▪ ]. However, the immune response mediated by innate immune cells, which acts early and upstream of adaptive immune response [7], has recently drawn significant attention in SLE pathogenesis [8,9 ▪ ]. The present review explores the complex associations between innate immune cells and SLE pathogenesis, with focus on neutrophils as these cells are found in large numbers and play critical immune functions [10 ▪ ]…”

SIRT2-PFKP interaction dysregulates phagocytosis in macrophages with acute ethanol-exposure

“…The effect of acute ethanol-exposure on glycolysis and glycolysis-regulating enzymes in immunosuppressed macrophages is not fully understood ( 9 , 33 , 38 ). Glycolytic enzymes are known to regulate basic cellular functions and immune response, in addition to the regulation of glycolysis ( 39 – 41 ). Specifically, the platelet isoform of phosphofructokinase (PFKP), a key glycolysis-regulating enzyme, serves as a protein kinase that regulates autophagy.…”