Associate Professor UTMB Galveston, Texas, United States
Abstract Text:
Background: Immune system uses a highly intriguing mechanism to polarize naïve macrophages (MФs) into pro-inflammatory, antimicrobial M1-MФs and anti-inflammatory, tissue repair mediating M2-MФs. To develop therapeutic strategies for uncontrolled MФ polarization, we analyzed the interplay between metabolism and epigenetics using a highly sensitive, multiplexed ‘triomics’. Hypothesis: We hypothesized that a crosstalk between ‘metabolism and epigenetic modifications’ determines MФ polarization essential for infection and inflammation control.
Methods: A novel ‘triomics’ method was used to analyze metabolites, histone modifications and protein expression concurrently from the same samples.
Results: (a) Acetylation and M1-MФ phenotype: TCA cycle maintained by replenishment of OAA through glutamate/aspartate metabolism, upregulated de novo synthesis of NAD+ from tryptophan metabolism and increased NAD+ production by oxidation of NADH via the mitochondrial respiratory complex I-derived Sirtuin-type histone deacetylase activity. Lower acetyl-CoA production from glycolysis and blocked acetyl release from NAA, NAG and NAO, and increased NAD+ synthesis or production appeared to be the major causes for reduction of histone global acetylation in M1-MФs. (b) Accumulation of Nα-Acetyl-Aspartate (NAA), -glutamate (NAG), and -ornithine (NAO) resulted in the trap of acetyl-CoA, which contributed to hypoacetylation of histones measured in M1-MФs. (c) We found that blocked one-carbon metabolism led to histone demethylation in M1-MФs.
Conclusions: Our data indicate that metabolite-altered histone acetylation, histone and RelA arginine methylation are promising targets for polarizing macrophages to control infection or inflammation.
