Targeting immunometabolism as an anti-inflammatory strategy

Abstract

The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

“…Chronic pathological disorders, including cardiovascular diseases (CVDs) [ 1 , 2 ], neurodegenerative diseases [ 3 , 4 ], diabetes [ 5 , 6 ], metabolic syndrome [ 7 , 8 ], and cancer [ 9 , 10 ] share an inflammatory microenvironment as a hallmark [ 11 ]. A Common feature of these complex diseases is the activation of “sterile” inflammatory pathways, in which immune cells represent relevant effectors and drivers for the onset and progression of the disease [ 12 ], due to their extreme capability to reshape their phenotype [ 13 ], to functionally [ 14 ], metabolically [ 15 , 16 ] adapting to the surrounding environment. Among these inflammatory-mediated disorders, CVDs account as the leading cause of death worldwide.…”

Indoxyl Sulfate-Mediated Metabolic Alteration of Transcriptome Signatures in Monocytes of Patients with End-Stage Renal Disease (ESRD)

“…An increasing body of evidence demonstrates that activated monocytes/macrophages strictly modulate their metabolic programs to meet the demands of participation in immune responses such as cytokine production, and that metabolites play important roles in epigenetic modifications [ 38 , 39 , 40 ]. Much focus recently has been on understanding the interconnection between metabolic reprogramming and immune function for discovering important therapeutic targets in many inflammatory disorders [ 40 , 41 , 42 , 43 ]. In diabetic CKD patients, systemic metabolic failure induced by obesity, insulin resistance, and β-cell dysfunction exacerbates the progression of renal disease [ 44 ].…”

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

“…LPS signaling in Mϕs drives a shift to aerobic glycolysis that appears to be critical for pro‐IL‐1β synthesis, as inhibiting glycolysis with 2‐deoxyglucose suppresses IL‐1β mRNA 121,122 . Further studies have identified multiple metabolites and metabolic pathways that regulate LPS induced pro‐IL‐1β production 123 . Targeting these metabolic pathways may indirectly impact NLRP3 transcriptional priming.…”