Immunometabolism in the pathogenesis of systemic lupus erythematosus: an update

Abstract

Purpose of review: To provide an update on state-of-the-art evidence on the role of immunometabolism reprogramming in the pathogenesis of systemic lupus erythematosus (SLE).

Recent findings: Mitochondrial dysfunction and enhanced oxidative stress, along with specific defects in other metabolic pathways, can promote dysregulation of innate and adaptive immune responses in SLE. These abnormalities appear to be driven by genetic and epigenetic factors, modulated by stochastic events. In addition to extensive descriptions of abnormalities in immunometabolism of lupus lymphocytes, recent studies support the critical role of dysregulation of metabolic pathways in innate immune cells including neutrophils, macrophages and dendritic cells, in SLE pathogenesis. Recent abnormalities described in lipid metabolism have been associated with SLE disease activity and related damage. Promising therapeutic strategies that target these metabolic abnormalities have recently been described in SLE.

Summary: Fundamental new insights regarding the role of mitochondrial dysfunction in innate immune dysregulation in SLE pathogenesis have recently emerged. Defects in specific molecular pathways pertinent to immunometabolism in SLE have been described. New insights in translational medicine and promising therapeutic targets have been proposed based on these recent findings.

Figure 1.. Mitochondrial dysfunction and oxidative stress in SLE.

Chronically increased OXPHOS in immune cells promotes enhanced generation of mROS and enhanced type I IFN responses. Excessive mROS synthesis promotes MAVS oligomerization in the MOM that is essential for antiviral immune responses but dysregulated in SLE. Enhanced oxidative stress along with a putative defective disassociation of mtDNA from TFAM in the mitochondrial matrix, facilitates the oxidation of mtDNA. Increased VDAC oligomers in the MOM interact with oxidized mtDNA fragments and facilitating their release into the cytoplasm, where they activate the cGAS-STING pathway and upregulate ISG expression. Additionally, autoantibodies to free-cell mtDNA may contribute to lupus immune dysregulation. Perturbations in immunometabolism pathways described in SLE are depicted in yellow boxes; novel therapeutic strategies targeting some of these specific defects are depicted in red boxes. cGAS-STING = cyclic guanosine monophosphate-–adenosine monophosphate synthase (cGAS)-Stimulator of Interferon Genes (STING); CoQ = coenzyme Q10; Cyt c = cytochrome c; IFNs = interferons; IRF-3 = Interferon regulatory factor 3; MAVS = mitochondrial antiviral stimulator; MDA-5 = melanoma differentiation-associated protein 5; mROS = mitochondrial reactive oxygen species (ROS); mtDNA = mitochondrial DNA; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; OXPHOS = oxidative phosphorylation; RIG-I = retinoic acid-inducible gene I; SLE = systemic lupus erythematosus; VDAC1 = voltage-dependent anion channel 1.

Figure 2.. Glycolysis, glutaminolysis and mTOR pathway defects in SLE.

Specific defects in immunometabolism pathways in SLE, such as mTOR, glycolysis and glutaminolysis, interact in an orchestrated manner to promote dysregulation of immune cells. GLUT1 and high glycolysis-related genes are enhanced in lupus. In addition, upregulation of mTOR pathway, increased levels of MCJ protein and enhanced CaMK4 (which binds to PKM2) perpetuate a highly glycolytic state in lymphocytes. The mTOR pathway is triggered by low levels of SRSF-1 protein which, in normal conditions promotes the expression of the negative regulator of mTORC1, PTEN. Treatment with metformin inhibits mTOR pathway and attenuates lupus-like disease by enhancing AMPK. In lupus Th17 cells, overexpressed CREM/ICER inhibits PDH enzymatic activity, which favors the shift from pyruvate to lactate instead of pyruvate to acetyl-CoA. Furthermore, CREM/ICER activates the glutaminolysis pathway, with a putative role in SLE, as the inhibition of the Gs1 enzyme attenuates lupus-like disease. Perturbations in immunometabolism pathways described in SLE are depicted in yellow boxes; novel therapeutic strategies targeting some of these specific defects are depicted in red boxes. Acetyl-CoA = acetyl coenzyme A; AMPK = AMP-activated protein kinase; CaMK4 = calcium/calmodulin-dependent protein kinase 4; cGAS-STING = cyclic guanosine monophosphate-–adenosine monophosphate synthase (cGAS)-Stimulator of Interferon Genes (STING); CREM/ICER = cAMP response element modulator/inducible cAMP early repressor; EZH2 = enhancer of zeste homolog 2; Gls1 = glutaminase 1; MCJ = methylation-controlled J protein; mTORC1 = mammalian target of rapamycin complex 1; PDH = pyruvate dehydrogenase; PKM2 = pyruvate kinase M2; PTEN = phosphatase and tensin homolog; SRSF1 = serine/arginine-rich splicing factor 1.