Integrated metabolism and epigenetic modifications in the macrophages of mice in responses to cold stress

Abstract

The negative effects of low temperature can readily induce a variety of diseases. We sought to understand the reasons why cold stress induces disease by studying the mechanisms of fine-tuning in macrophages following cold exposure. We found that cold stress triggers increased macrophage activation accompanied by metabolic reprogramming of aerobic glycolysis. The discovery, by genome-wide RNA sequencing, of defective mitochondria in mice macrophages following cold exposure indicated that mitochondrial defects may contribute to this process. In addition, changes in metabolism drive the differentiation of macrophages by affecting histone modifications. Finally, we showed that histone acetylation and lactylation are modulators of macrophage differentiation following cold exposure. Collectively, metabolism-related epigenetic modifications are essential for the differentiation of macrophages in cold-stressed mice, and the regulation of metabolism may be crucial for alleviating the harm induced by cold stress.

Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues

“…This results in the delayed activation of the M2 characteristic genes such as Arg-1 and the M2 core transcription factor STAT6, both of which are regulated by H3K18 histone lactylation. Eventually, the M2 anti-inflammatory phenotype manifests in macrophages ( 21 , 111 ). In addition, as mentioned previously, lactate accumulated in macrophages can exert an inhibitory effect on aerobic glycolysis through non-histone lactylation modifications: (1) Non-enzymatic lysine lactoylation of glycolytic enzymes can limit aerobic glycolysis by inhibiting enzyme activity ( 28 ); (2) Lactylation of PKM2 can both increase its activity and inhibit its nuclear translocation, thus reducing aerobic glycolysis ( 101 ).…”

Post-translational protein lactylation modification in health and diseases: a double-edged sword

“…B Three types of interactions (in different color blocks) between lactylation (pink residues with La) and other PTMs (green residues with R) are shown can trigger metabolic reprogramming of aerobic glycolysis driven by mitochondrial damage in macrophages, increase histone acetylation to promote the release of inflammatory factors. In turn, the accumulation of intracellular lactate results in histone lactylation as a selfprotective mechanism to initiate the transcription of anti-inflammatory genes [60]. However, the changes of Kla and Kac differ across cell types.…”

The role and mechanism of histone lactylation in health and diseases

“…Additionally, when glucose is used as a treatment, the levels of lactylation and acetylation both increase within a certain limit ( Zhang et al, 2019 ). Mice that are exposed to cold also have higher levels of lactylation and acetylation ( Lu et al, 2022 ). Lactylation and acetylation levels under hypoxia, however, differ depending on the type of cell; in Hela cells, lactylation levels increase, while acetylation levels decrease.…”