Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation
Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.
Authors
- Huan Yan (ORCID: https://orcid.org/0000-0001-8744-8665)
- Ke‐Qiong Deng (ORCID: https://orcid.org/0000-0003-2406-7456)
- Yanfang Zhu (ORCID: https://orcid.org/0000-0002-8606-0869)
- Shuo Rong (ORCID: https://orcid.org/0000-0001-9986-5626)
- Xiaoyu Chen (ORCID: https://orcid.org/0000-0002-1486-6329)
- Ke Xu (ORCID: https://orcid.org/0000-0002-9969-3681)
- Zhibing Lu (ORCID: https://orcid.org/0000-0002-7950-3465)
- Aihua Liao (ORCID: https://orcid.org/0000-0001-8533-8315)
- Huanhuan Cai (ORCID: https://orcid.org/0000-0003-3426-8630)
- Lin Zhang (ORCID: https://orcid.org/0000-0003-0018-3903)
- Wei Xiong (ORCID: https://orcid.org/0000-0002-3624-4504)
- Hao Zeng (ORCID: https://orcid.org/0000-0002-2061-6350)
- Yan Liu (ORCID: https://orcid.org/0000-0002-1518-7264)
- Shi Liu (ORCID: https://orcid.org/0000-0002-9289-0631)
- Fubing Wang (ORCID: https://orcid.org/0000-0002-5971-2622)
- Li Zhou (ORCID: https://orcid.org/0000-0002-6736-0057)
- Cihang Guo
- Zelong Li
- Zeng Cai (ORCID: https://orcid.org/0000-0001-5398-7193)
- Hong Ren (ORCID: https://orcid.org/0000-0003-3156-6640)
- Xueyuan Chen (ORCID: https://orcid.org/0000-0003-0493-839X)
- Xiangtai Zeng
- Gechang Zhong
- Ying-Bo Chen
Institutions
- Chinese PLA General Hospital (CN)
- Wuhan University (CN)
- Shanghai Children's Medical Center (CN)
- Wuhan Institute of Virology (CN)
- Zhongnan Hospital of Wuhan University (CN)
- Stomatology Hospital (CN)
- First Affiliated Hospital of Gannan Medical University (CN)
- Shanghai Children's Hospital (CN)
- Hainan 301 Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-04
- DOI
- https://doi.org/10.1038/s41467-025-58563-2
- Citations
- 47
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 37.48
Funders
- National Natural Science Foundation of China
- Science and Technology Department of Hubei Province
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities