Immunometabolism: An Overview and Therapeutic Prospects in Autoimmune Diseases

Abstract

Metabolism is a critical immune regulator under physiologic and pathologic conditions. Culminating evidence has disentangled the contribution of distinct metabolic pathways, namely glucolysis, pentose phosphate, fatty acid oxidation, glutaminolysis, Krebs cycle and oxidative phosphorylation, in modulating innate and adaptive immune cells based on their activation/differentiation state. Metabolic aberrations and changes in the intracellular levels of specific metabolites are linked to the inflammatory phenotype of immune cells implicated in autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and diabetes. Notably, targeting metabolism such as the mTOR by rapamycin, hexokinase by 2-deoxy-D-glucose, AMP-activated protein kinase by metformin, may be used to ameliorate autoimmune inflammation. Accordingly, research in immunometabolism is expected to offer novel opportunities for monitoring and treating immune-mediated diseases.

Re-analysis of SARS-CoV-2 infected host cell proteomics time-course data by impact pathway analysis and network analysis. A potential link with inflammatory response

“…Two proteins from the neomycin, kanamycin and gentamicin biosynthesis pathway resulted upregulated at 24 h after virus infection (Figure 1b): HK1 (hexokinase 1) and HKDC1 (hexokinase domain containing 1), which are proteins related to glucose use and homeostasis 16,17 . Interestingly, HK has been previously associated with inflammatory response in autoimmune disorders, and, deoxy-D-glucose (2-DG), an inhibitor of HK, has been proposed to ameliorate autoimmune inflammation 18 . Recently, 2-DG has been shown to inhibit SARS-CoV-2 replication in Caco-2 cells 10 and to inhibit rhinovirus infection and inflammation in a murine model 19 .…”

Metabolic Targets for Treatment of Autoimmune Diseases

“…This ultimately suggests more longstanding benefits of longterm sirolimus administration. The treatment with NAC blocked the activation of mTORC1 that appears to be exceedingly high in doublenegative T cells [5], which produce pro-inflammatory cytokines, such as IL-4 and IL-17 [107]. In contrast to SLE, mitochondrial oxidative stress appears to be reduced in RA due to increased NADPH production through the PPP, as shown in Figure 4.…”

“…Enhanced mitochondrial metabolism, such as mitochondrial hyperpolarization [3] and block in electron transport [4] occur with increased production of reactive oxygen intermediates (ROI) and the depletion of antioxidant metabolites, such as reduced glutathione [3]. The rate-limiting constituent of de novo reduced glutathione (GSH) production is cysteine, which can be replaced with a cell-permeable precursor, Nacetyl cysteine (NAC) [5]. NADPH that is required to maintain GSH in reduced form was also depleted in SLE and more over cysteine itself was depleted in lymphocytes of SLE patients that provide a clear rationale for its therapeutic replacement [60].…”

“…Metabolic pathways govern the lineage specification [2]. With consideration to immune cells, the metabolic signature is known to change depending on stages of development and pathological conditions, whether they are in quiescent, activated, or, memory state [3][4][5]. In this review, we provide an update on the current understanding of the metabolic signatures noted within different immune cells of many different autoimmune diseases with a focus on selecting pathways and specific metabolites as targets for treatment.…”

“…restoration of intracellular GSH with NAC corrected Tcell dysfunction, such as depletion of regulatory T cells and reduced anti-DNA production[5].Contrary to SLE, in rheumatoid arthritis ROS and oxidative burst offers protection from arthritis and reduced ROS production, NADPH oxidase (NOX) 2 deficiency associated with increased severity of joint inflammation[61]. Depletion of GSH can activate mTOR and studies targeting rapamycin have proven safety and efficacy in SLE[62].Podosome scaffolding protein TKS5 increases the invasive capabilities of RA T lymphocytes by forming tissue-invasive membrane structures[68].TKS5 overexpression is driven by reduced glycolytic flux, increased fatty acid synthesis and reduction in fatty acid synthesis reverses it.…”