Metabolic Targets for Treatment of Autoimmune Diseases

Abstract

There is a considerable unmet demand for safe and efficacious medications in the realm of autoimmune and inflammatory diseases. The fate of the immune cells is precisely governed by control of various metabolic processes such as mitochondrial oxidative phosphorylation, glycolysis, fatty acid synthesis, beta-oxidation, amino acid metabolism, and several others including the pentose phosphate pathway, which is a unique source of metabolites for cell proliferation and maintenance of a reducing environment. These pathways are tightly regulated by the cytokines, growth factors, availability of the nutrients and host-microbe interaction. Exploring the immunometabolic pathways that govern the fate of cells of the innate and adaptive immune system, during various stages of activation, proliferation, differentiation and effector response, is crucial for new development of new treatment targets. Identifying the pathway connections and key enzymes will help us to target the dysregulated inflammation in autoimmune diseases. The mechanistic target of rapamycin (mTOR) pathway is increasingly recognized as one of the key drivers of proinflammatory responses in autoimmune diseases. 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.

Keywords: acetylcysteine; glycolysis; immune metabolic pathways; kynurenine; mechanistic target of rapamycin; oxidative phosphorylation; oxidative stress; pentose phosphate pathway; psoriasis; rheumatoid arthritis; scleroderma; systemic lupus erythematosus; tryptophan.

Figure 1.

This schematic diagram shows the metabolic pathways controlling activation and lineage specification in the immune system. Depicts how various metabolic pathways regulate the surface receptors, and intracellular transducers in immune cells. Electron transport chain blockage results in elevated mitochondrial transmembrane potential (Δᴪm) or mitochondrial hyperpolarization, and diminished mitophagy contributes to accumulation of oxidative stress-generating mitochondria and depletion of ATP and glutathione. Reactive oxygen species (ROS) are generated by electron transfer to O₂ at complex I. These metabolic changes underlie the activation of mTORC1, which promotes glycolysis in CD4⁺ T cells, further enhancing accumulation of mitochondria in necrosis prone, pro inflammatory double negative (DN) T cells and depleting Treg cells. The direction of signaling is indicated by arrow (red = increase, blue = decrease). Drugs that affect metabolism are shown in green. IL 6 = interleukin-6, NAC = N-acetyl cysteine; Drp1 = dynamine-related protein 1; HCQ = hydroxychloroquine; TCA = tricarboxylic acid; 2 DG = 2 Deoxy glucose; Acetyl-CoA = acetyl co enzyme A; VLDLR = very low density lipoprotein receptor; MMF = mycophenolate mofetil; LDLR = low density lipoprotein receptor; G6P = glucose-6-phosphate; PPP = pentose phosphate pathway; G6PD = glucose-6-phosphate dehydrogenase; 6PGL = 6-phosphogluconolactonase; GSSG= oxidized glutathione; TAL = transaldolase; 6PG = 6-phosphonogluconate; 6PGD = 6-phosphogluconate dehydrogenase; AMPK = AMP dependent protein kinase; PI3K = phosphatidylinositol 3 kinase; R5P = ribose-5-phosphate; PD-1 = programmed death 1;Tfh = follicular helper T cells. Reproduced from [12], an open access article distributed under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

Figure 2.

Metabolic control of T-cell related to tryptophan metabolism. Inflammatory cytokines like interferon known to enhance expression of key enzyme IDO. This results in tryptophan depletion as majority of the resident tryptophan is metabolized via KP, and increase in KYN. Depletion of Tryptophan activates the GCN2 kinase pathway and inhibits mTOR pathway. KYN can enhance AhR/mTOR activity, and may increase the risk of thrombosis in anti-phospholipid syndrome. KYN also through AhR/mTOR can increase Th17 differentiation and block Treg differentiation. GCN2 kinase pathway can inhibit mTOR activity and enhance autophagy. IDO inhibitors, mTOR inhibitors, and GCN2 agonist are some of the potential targets in this pathway that can be utilized to treat autoimmune diseases. Note: KYN = Kynurenine, KP = KYN pathway; IDO = indoleamine 2,3-dioxygenase; AhR = aryl hydrocarbon receptor; mTOR = mammalian target of rapamycin; GCN 2 = General Control Nonderepressible; TNF = tumour necrosis factor, IL = interleukin; IFN = interferon.

Figure 3.

cGAS-STING-IFN pathway activation in SLE. The exogenous cyclic GMP–AMP dinucleotide (2′3′cGAMP) released by bacteria or tumors is imported through the reduce folate career transporter SLC19A1 into the cell. cGAS binds to cytosolic DNA and results in endogenous cGAMP production. Both the exogenous and endogenous cGAMP binds to STING adapter protein and induces transcription of type 1 interferon, the major mediator in SLE pathogenesis. TREX 1, DNAse 1 mutations in humans, results in DNA accumulation and increased susceptibility to SLE like syndromes. SLC19A1 is a potential target to control SLE disease activity and existing drugs like folate, methotrexate, and sulfasalazine known to inhibit it in studies.

Figure 4.

Discordant changes in mitochondrial metabolic pathways in patients with RA and SLE. In RA T cells glucose is shunted more towards PPP pathway leading to increased NADPH and reduced ROS production and sensing that underlie ATM deficiency. In turn, ATM deficiency promotes pathogenic Th1 and Th17 differentiation and production of inflammatory cytokines. Reduced glycolysis in RA T cells is attributed to PFKFB3 deficiency and thus fatty acid synthesis and TKS5 production are increased. TKS5 helps in T cell invasion and migration. Low NMT in RA T cells result in low AMPK activation leading to unopposed mTORC1 activation. Increased glycolysis and lactate uptake via SLC5A12 elicit Th17 expansion. Low MRE11A in mitochondria can lead to mitochondrial DNA leakage resulting in activation of inflammasome (AIM2 and NLRP3) and caspase-dependent production of IL-1 and IL-18. In SLE T cells, genetically enforced increased expression of HRES-1/Rab4 causes depletion of Drp1, reduced mitophagy, accumulation of oxidative stress-generating mitochondria [37] and activation of mTORC1 [121]. Oxidative stress will result in NADPH and glutathione depletion. mTORC1 activation leads to increased glycolysis, glucose utilization and facilitates Th1, Th17 and Tfh differentiation. Increased endogenous cGAMP produced via cGAS and exogenous cGAMP uptaken via SLC19A1 can activate STING and promotes type I interferon production. Accumulation of kynurenine also activates mTORC1. mTOR activation and oxidative stress are most prominent in double negative (DN) T cells that release necrotic debris [29]. Accumulation of mitochondrial occurs with mitochondrial hyperpolarization that results in ATP depletion and increased ROS production [44]. Mitochondrial DNA can leak via voltage dependent anion channels (VDAC) oligomerization can increase type 1 interferon production.