Targeting Metabolism as a Novel Therapeutic Approach to Autoimmunity, Inflammation, and Transplantation

Abstract

Immune cell activation and differentiation occurs concurrently with metabolic reprogramming. This insures that activated cells generate the energy and substrates necessary to perform their specified function. Likewise, the metabolic programs amongst different cells of the immune system vary. By targeting different metabolic pathways, these differences allow for selective regulation of immune responses. Further, the relative susceptibility of cells to a metabolic inhibitor is dictated by their metabolic demands; cellular selectivity is based on demand. Therefore where differences exist in metabolic pathways between healthy and pathogenic cells, there is opportunity for selective regulation with agents lacking intrinsic specificity. There are now a host of studies demonstrating how inhibitors of metabolism (for example glycolysis, glutamine metabolism, and fatty acid oxidation) can regulate immune responses and treat immune mediated pathogenesis. In this brief review we detail how inhibitors of metabolism can be employed to regulate immune responses in both autoimmunity and transplantation.

Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity

“…This suggests that specific metabolic profiles govern the phenotype of T cell subsets (Geltink et al, 2018). Importantly, previous studies indicate that interfering with intracellular metabolic pathways in immune cells represents a novel attractive therapeutic approach in inflammation (O'Neill et al, 2016;Freitag et al, 2016;Bettencourt and Powell, 2017).…”

From sepsis to acute respiratory distress syndrome (ARDS): emerging preventive strategies based on molecular and genetic researches

“…According to the present understanding of the pathogenesis of ARDS, immunometabolism controls the development of inflammation in patients with sepsis-induced ARDS by regulating the function of immune cells [31]. Although, the discoveries and advances targeting immune cells as an alternative approach for ARDS therapy have been reported recently, improved outcome and decreased mortality rates in patients with sepsis-related ARDS have not been explicitly described [32,33].…”

Integrative computational approach identifies new targets in CD4+ T cell-mediated immune disorders

“…15 Several studies have recently demonstrated the potential for drug repurposing in CD4+ T cell-mediated diseases. 16,17 For example, 2-deoxy-Dglucose (anticancer agent) and metformin (antidiabetic drug) were shown to reverse SLE in a mouse model. 14 However, drug repurposing, as well as drug discovery and development efforts for targeting T cell metabolism have been limited due the lack of knowledge about the key molecular targets in this context.…”