Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation

Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during disease states. The production of lactic acid in the gut microenvironment is vital for tissue homeostasis. In the present study, we examined how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory response. We found that lactic acid serves as a primary fuel source to promote histone H3K27 acetylation, which allows the expression of immunosuppressive gene program including Nr4a1. Consequently, macrophage pro-inflammatory function was transcriptionally repressed. Furthermore, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression (“trained immunosuppression”). Pre-exposure to lactic acid induces lipopolysaccharide tolerance. These findings thus indicate that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment. [Display omitted] •Lactic acid is metabolized by macrophages to fuel the TCA cycle•Citrate production from lactic acid promotes histone H3K27 acetylation•Histone acetylation by lactic acid leads to immunosuppressive gene expression•Nr4a1 expression facilitates lactic acid to develop long-term immunosuppression Lactic acid is emerging as a prominent immunosuppressive metabolite. Shi et al. reveal that lactic acid acts as a primary fuel source for the TCA cycle to promote H3K27 acetylation. This histone modification allows the expression of an immunosuppressive gene program including Nr4a1 that consequently inhibits macrophage pro-inflammatory response.