Metabolic pathways mediate pathogenesis and offer targets for treatment in rheumatic diseases

Abstract

Purpose of review: The cause of autoimmune diseases remains incompletely understood. Here, we highlight recent advances in the role of proinflammatory metabolic pathways in autoimmune disease, including treatment with antioxidants and mechanistic target of rapamycin (mTOR) inhibitors.

Recent findings: Recent studies show that mTOR pathway activation, glucose utilization, mitochondrial oxidative phosphorylation, and antioxidant defenses play critical roles in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, immune thrombocytopenia, Sjögren's syndrome, large vessel vasculitis, and systemic lupus erythematosus. mTOR activity leads to Th1 and Th17 cell proliferation, Treg depletion, plasma cell differentiation, macrophage dysfunction, and increased antibody and immune complex production, ultimately resulting in tissue inflammation. mTOR also affects the function of connective tissue cells, including fibroblast-like synoviocytes, endothelial cells, and podocytes. mTOR inhibition via rapamycin and N-acetylcysteine, and blockade of glucose utilization show clinical efficacy in both mouse models and clinical trials, such as systemic lupus erythematosus.

Summary: The mTOR pathway is a central regulator of growth and survival signals, integrating environmental cues to control cell proliferation and differentiation. Activation of mTOR underlies inflammatory lineage specification, and mTOR blockade-based therapies show promising efficacy in several autoimmune diseases.

Figure 1.

mTOR activity contributes to autoimmune disease. A) mTORC1 and mTORC2 are distinct complexes that integrate environmental cues to shape cellular phenotype. mTORC1 senses a variety of signals including amino acid sufficiency, glucose sufficiency, cytokines, growth hormones, and cellular energy, and controls mRNA transcription, protein, nucleotide, and lipid synthesis, and metabolic changes within the cell. mTORC2 signaling is less characterized, but activation occurs downstream of the PI3K/AKT pathway. mTORC2 has roles primarily in cytoskeletal reorganization, although it also has roles in apoptosis, ion transport, and glucose metabolism, among others. B) The mTOR pathway is implicated in a variety of autoimmune diseases via controlling cellular development. mTOR activity skews immune cells towards a pro-inflammatory phenotype, as well promoting proliferation in other cell lineages, ultimately promoting disease pathogenesis. TKR = Tyrosine kinase receptor. ROS = Reactive oxidative species. RAPA = Rapamycin. PPP = Pentose phosphate pathway. DC = Dendritic cell. M0 = Macrophage. FLS = Fibroblast-like synoviocyte. MKC = Megakaryocyte. EC = Endothelial cell. SLE = Systemic lupus erythematosus. APS = Antiphospholipid syndrome. PsA = Psoriatic arthritis. AS = Ankylosing spondylitis. RA = Rheumatoid arthritis. ITP = Immune thrombocytopenia.