Metabolic-epigenetic rewiring of CCR5 hi monocytes sustains long-term trained immunity against lethal sepsis

Trained immunity enhances innate host defense by endowing monocytes with memory-like properties, yet the underlying integrated metabolic and epigenetic mechanisms remain elusive. Here, we demonstrate that coimmunization with Bacille Calmette-Guérin (BCG) and bacterial lipoprotein (BLP) induces a durable form of trained immunity that provides robust, long-term protection against polymicrobial sepsis from early life into adulthood. Single-cell RNA sequencing revealed that this effect is mediated by an expansion of CCR5 hi memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG + BLP vaccination activated the AKT–mTOR–HIF-1α axis, driving glycolytic reprogramming and lactate accumulation. Elevated lactate enhanced KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. In addition, BCG + BLP stimulation of human cord blood mononuclear cells induced CCR5 hi monocytes that recapitulated trained immunity features. These findings identify a lactate-KAT2B-H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5 hi monocytes, highlighting CCR5 hi monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis.

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Publication Details

Journal
Science Advances
Published
2026-08-21
DOI
https://doi.org/10.1126/sciadv.aee1634
Primary Topic
Immune responses and vaccinations
Type
article
Field-Weighted Citation Impact
0.00

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article

Metabolic-epigenetic rewiring of CCR5 hi monocytes sustains long-term trained immunity against lethal sepsis

Lingqi Xu, Wenyan Hao, Huiting Zhou, Yuan Gong et al.
Science Advances
Immune responses and vaccinations
article

Metabolic-epigenetic rewiring of CCR5 hi monocytes sustains long-term trained immunity against lethal sepsis

Lingqi Xu, Wenyan Hao, Huiting Zhou, Yuan Gong, Qiang Shan, Daolin Tang, Timothy R. Billiar, Yiben Yang, Rui Kang, Jian Wang, Haichao Wang, Jie Huang, Zhenjiang Bai, Yifang Ding, Jiang Huai Wang, Yaoshuang Li, Yu Wang
article en

Abstract

Trained immunity enhances innate host defense by endowing monocytes with memory-like properties, yet the underlying integrated metabolic and epigenetic mechanisms remain elusive. Here, we demonstrate that coimmunization with Bacille Calmette-Guérin (BCG) and bacterial lipoprotein (BLP) induces a durable form of trained immunity that provides robust, long-term protection against polymicrobial sepsis from early life into adulthood. Single-cell RNA sequencing revealed that this effect is mediated by an expansion of CCR5 hi memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG + BLP vaccination activated the AKT–mTOR–HIF-1α axis, driving glycolytic reprogramming and lactate accumulation. Elevated lactate enhanced KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. In addition, BCG + BLP stimulation of human cord blood mononuclear cells induced CCR5 hi monocytes that recapitulated trained immunity features. These findings identify a lactate-KAT2B-H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5 hi monocytes, highlighting CCR5 hi monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis.

Science AdvancesVol. 12(34)
Feinstein Institute for Medical Research (US), University of Pittsburgh (US), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), University College Cork (IE), Cork University Hospital (IE), Soochow University (CN), Southwestern Medical Center (US), Suzhou Institute of Systems Medicine (CN), Children's Hospital of Suzhou University (CN), Southwestern Medical Center (US), The University of Texas Southwestern Medical Center (US)
National Natural Science Foundation of China, Natural Science Foundation of Jiangsu Province
Openalex Percentile: Top 16%
Immune responses and vaccinations
DOIOpen Access PDFOpenAlex
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