Lactate induces metabolic and epigenetic reprogramming of pro‐inflammatory Th17 cells

Abstract

Increased lactate levels in the tissue microenvironment are a wellknown feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. Here, we demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating the metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROSdriven IL-2 secretion. Moreover, we observed increased levels of genome-wide histone H3K18 lactylation, a recently described marker for active chromatin in macrophages, in lactate-treated Th17 cells. In addition, we show that high lactate concentrations suppress Th17 pathogenicity during intestinal inflammation in mice. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotypes into regulatory T cells.

Novel Insight of Nitrogen Deprivation Affected Lipid Accumulation by Genome-Wide Lactylation in Nannochloropsis oceanica

“…K, A, and methionine (M) residues were also often identified upstream of the Kla sites, whereas K, A, and G residues were more commonly observed downstream of the Kla sites. 17,35,37,38 These results demonstrated that some motifs in N. oceanica are conserved with other organisms, including higher plant rice, T. gondii, and B. cinerea, which implies that proteinlactylated modification is evolutionally conserved.…”

“…Certain amino acid residues around the Kla were found to be significantly enriched when evaluating the motif sequences in an enrichment heat map (Figure C,D). K, A, and methionine (M) residues were also often identified upstream of the Kla sites, whereas K, A, and G residues were more commonly observed downstream of the Kla sites. ,,, These results demonstrated that some motifs in N. oceanica are conserved with other organisms, including higher plant rice, T. gondii, and B.…”

“…One possibility is the direct lactylation of glycolytic enzymes. Histone lactylations, on the other hand, can enrich near the promoters of several glycolytic genes, where they serve a vital part as regulators of glycolysis. , …”

“…Histone lactylations, on the other hand, can enrich near the promoters of several glycolytic genes, where they serve a vital part as regulators of glycolysis. 16,37 Protein, carbohydrate, and lipid metabolisms are all linked via the TCA cycle, which takes place in the mitochondria and generates NADH/FADH2 for ATP synthesis. Many TCA cycle enzymes in N. oceanica exhibited a significant increase in their proteins, including malate dehydrogenase (MDH; NO09G03170), SDH (NO29G00740, NO01G05020, and N O 0 1 G 0 1 5 3 0 ) , S C A ( N O 0 6 G 0 3 8 1 0 ) , O G D H (NO16G00280 and NO19G01350), and aconitate hydratase (ACH; NO02G04110) (Figure 5A and Supporting Information), suggesting an overall TCA cycle upregulation stimulated by ND.…”

Yogurt Alleviates Imiquimod-Induced Psoriasis by Activating the Lactate/GPR81 Signaling Axis in Mice

“…17,39 In addition, lactate has been revealed to function as a negative feedback signal to control immune cell metabolism, preventing overactive inflammatory response. 22,40,41 In general, our study has explored a novel application of lactate as an antiinflammatory agent and provided a possible explanation for yogurt as a potential dietary intervention strategy for people with psoriasis.…”