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Shi, W., Cassmann, T. J., & Bhagwate, A. V. Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation. Cell Reports. Added by: Dr. Enrique Feoli (05/07/2025, 21:34) Last edited by: Dr. Enrique Feoli (05/07/2025, 21:51) |
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| Resource type: Journal Article ID no. (ISBN etc.): 2211-1247 BibTeX citation key: Shi View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Microbiota on immunity Keywords: CP: Immunology, CP: Metabolism, Epigenetic reprogramming, histone acetylation, immunosuppression, inflammation, inflammatory bowel disease, lactic acid, macrophage, Metabolism, metabolite sensing, tissue microenvironment Creators: Bhagwate, Cassmann, Shi Collection: Cell Reports |
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Conclusiones
In summary, our study reveals a mechanism of lactic acid in suppressing macrophage pro-inflammatory response. We propose that lactic acid serves as a primary fuel source for TCA cycle metabolism to regulate H3K27ac enhancer repertoire, leading to the upregulation of lactic acid-specific gene program including Nr4a1, which in turn transcriptionally represses macrophage pro-inflammatory function. Note that this epigenetic reprogramming by lactic acid has a significant effect on promoting a form of long-term immunosuppression that leads to LPS tolerance in macrophages. These findings thus indicate that lactic acid sensing and its epigenetic reprogramming in macrophages represent a key homeostatic mechanism that promotes tolerogenic tissue microenvironment. Therapeutic targeting of the lactic acid-induced trained immunosuppression in macrophages therefore could be beneficial for treatment or prevention of inflammatory diseases.
Added by: Dr. Enrique Feoli |
| Abstract |
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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.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |
