A cellular overview of immunometabolism in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterised by a breakdown of immune tolerance and the development of autoantibodies against nucleic self-antigens. Immunometabolism is a rapidly expanding scientific field investigating the metabolic programming of cells of the immune system. During the normal immune response, extensive reprogramming of cellular metabolism occurs, both to generate adenosine triphosphate (ATP) and facilitate protein synthesis, and also to manage cellular stress. Major pathways upregulated include glycolysis, oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway (PPP), among others. Metabolic reprogramming also occurs to aid resolution of inflammation. Immune cells of both patients with SLE and lupus-prone mice are characterised by metabolic abnormalities resulting in an altered functional and inflammatory state. Recent studies have described how metabolic reprogramming occurs in many cell populations in SLE, particularly CD4+ T cells, for example favouring a glycolytic profile by overactivation of the mechanistic target of rapamycin (mTOR) pathway. These advances have led to an increased understanding of the metabolic changes affecting the inflammatory profile of T and B cells, monocytes, dendritic cells, neutrophils, and how they contribute to autoimmunity and SLE pathogenesis. In the current review, we aim to summarise recent advances in the field of immunometabolism involved in SLE, and how these could potentially lead to new therapeutic strategies in the future.

Blood RNA-sequencing across the continuum of ANA-positive autoimmunity reveals insights into initiating immunopathology

“…Most apparent was downregulation of mitochondrial complex I/NADH dehydrogenase activity suggesting potential derangements in oxidative phosphorylation. Metabolic reprogramming has been extensively described across a range of cell types in SLE and other autoimmune diseases 29. Evidence at transcriptomic level for altered cellular energy status and mitophagy in the subclinical phase is also emerging, with effects influenced by cell type and with disease transition 30.…”

“…Evidence at transcriptomic level for altered cellular energy status and mitophagy in the subclinical phase is also emerging, with effects influenced by cell type and with disease transition 30. Mitochondrial stress is proinflammatory31 but the relationship between mitochondrial dysfunction and IFN-I response appears complex and cell specific 29. Immune complexes involving ribonucleoprotein are potent induces of mitochondrial ROS and superoxide,32 leading to loss of mitochondrial membrane potential and extrusion of oxidised mitochondrial DNA (mtDNA)33 where it is a component of low-density granulocytes NETosis in SLE 32.…”

The causal relationship between autoimmune diseases and age-related macular degeneration: A two-sample mendelian randomization study

“…Furthermore, each autoimmune disease presents unique immune and inflammatory response characteristics. For instance, SLE may involve a broad autoimmune response [ 37 ], which, while systemic, does not directly impact the retinal cells as seen in AMD. In contrast, IBD is associated with local intestinal inflammation and could have secondary effects on the eye such as episcleritis, uveitis, and scleritis, which are distinct from the pathogenesis of AMD [ 38 ].…”