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.

Identification of Metabolic Biomarkers in Relation to Methotrexate Response in Early Rheumatoid Arthritis

“…Especially the Warburg effect, describing a shift towards inefficient energy production through aerobic glycolysis, and well recognized for its impact on drug response in cancer cells [ 44 ], has been extensively described in RA patients, as well as the upregulation of glycolysis [ 45 , 46 , 47 , 48 , 49 ]. As these processes have been associated with a proinflammatory state, targeting the Warburg effect or glycolysis has been suggested as a potential RA therapy [ 50 , 51 , 52 , 53 ]. However, these processes have, to date, not been linked to the response to existing therapies in RA.…”

Control of T Cell Metabolism by Cytokines and Hormones

“…The effect of TGF-β on T cell metabolism in an inflammatory disease context is largely unexplored. Understanding the mechanisms of cytokine-mediated metabolic reprogramming in T cells may lead to new therapeutic targets in selectively modulating metabolic pathways in order to control T cell pathogenesis, an approach that has shown promise in studies so far ( 124 ).…”

Transcription Factors Interplay Orchestrates the Immune-Metabolic Response of Leishmania Infected Macrophages

“…Different small molecules targeting metabolic processes in immune cells as a strategy to limit inflammation and change the outcome of inflammatory and autoimmune diseases are currently in use clinically ( Pålsson-McDermott and O’Neill, 2020 ). Hence, the majority of available or under development anti-rheumatic drugs, target various metabolites in immune cells belonging to purine, pyrimidine or GSH metabolism ( Piranavan et al., 2020 ). The host directed therapies includes different promising treatment strategies targeting macrophages’ polarization to the M2 phenotype that have been found associated with atherosclerosis regression and different compound are being tested to develop more efficient antiatherosclerosis therapy ( Bi et al., 2019 ).…”