Epigenetic mechanisms of Immune remodeling in sepsis: targeting histone modification

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Abstract

Sepsis is a life-threatening disorder disease defined as infection-induced dysregulated immune responses and multiple organ dysfunction. The imbalance between hyperinflammation and immunosuppression is a crucial feature of sepsis immunity. Epigenetic modifications, including histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA, play essential roles in regulating sepsis immunity through epi-information independent of the DNA sequence. In recent years, the mechanisms of histone modification in sepsis have received increasing attention, with ongoing discoveries of novel types of histone modifications. Due to the capacity for prolonged effects on immune cells, histone modifications can induce immune cell reprogramming and participate in the long-term immunosuppressed state of sepsis. Herein, we systematically review current mechanisms of histone modifications involved in the regulation of sepsis, summarize their role in sepsis from an immune perspective and provide potential therapeutic opportunities targeting histone modifications in sepsis treatment.

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Metabolic regulation of gene expression by histone lactylation

Di Zhang, Zhanyun Tang, He Huang … (2019)

The Warburg effect, originally describing augmented lactogenesis in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, macrophage polarization, and T-cell activation. This phenomenon is intimately linked with multiple diseases including neoplasia, sepsis, and autoimmune diseases 1,2 . Lactate, a compound generated during Warburg effect, is widely known as an energy source and metabolic byproduct. However, its non-metabolic functions in physiology and disease remain unknown. Here we report lactate-derived histone lysine lactylation as a new epigenetic modification and demonstrate that histone lactylation directly stimulates gene transcription from chromatin. In total, we identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce production of lactate through glycolysis that in turn serves as precursor for stimulating histone lactylation. Using bacterially exposed M1 macrophages as a model system, we demonstrate that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, elevated histone lactylation induces homeostatic genes involved in wound healing including arginase 1. Collectively, our results suggest the presence of an endogenous “lactate clock” in bacterially challenged M1 macrophages that turns on gene expression to promote homeostasis. Histone lactylation thus represents a new avenue for understanding the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

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Sepsis and septic shock

Laura Evans, Mitchell Levy, Andrew Rhodes … (2018)

Sepsis is a common condition that is associated with unacceptably high mortality and, for many of those who survive, long-term morbidity. Increased awareness of the condition resulting from ongoing campaigns and the evidence arising from research in the past 10 years have increased understanding of this problem among clinicians and lay people, and have led to improved outcomes. The World Health Assembly and WHO made sepsis a global health priority in 2017 and have adopted a resolution to improve the prevention, diagnosis, and management of sepsis. In 2016, a new definition of sepsis (Sepsis-3) was developed. Sepsis is now defined as infection with organ dysfunction. This definition codifies organ dysfunction using the Sequential Organ Failure Assessment score. Ongoing research aims to improve definition of patient populations to allow for individualised management strategies matched to a patient's molecular and biochemical profile. The search continues for improved diagnostic techniques that can facilitate this aim, and for a pharmacological agent that can improve outcomes by modifying the disease process. While waiting for this goal to be achieved, improved basic care driven by education and quality-improvement programmes offers the best hope of increasing favourable outcomes.

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The language of covalent histone modifications.

B. D. Strahl, C Allis (2000)

Histone proteins and the nucleosomes they form with DNA are the fundamental building blocks of eukaryotic chromatin. A diverse array of post-translational modifications that often occur on tail domains of these proteins has been well documented. Although the function of these highly conserved modifications has remained elusive, converging biochemical and genetic evidence suggests functions in several chromatin-based processes. We propose that distinct histone modifications, on one or more tails, act sequentially or in combination to form a 'histone code' that is, read by other proteins to bring about distinct downstream events.

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Author and article information

Contributors

Hao Zhang:

ORCID: http://orcid.org/0000-0001-5973-7080

eliteromes@126.com

Changhong Miao: miaochanghong_zs@163.com

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 11 February 2023

Publication date PMC-release: 11 February 2023

Publication date Collection: February 2023

Volume: 14

Issue: 2

Electronic Location Identifier: 112

Affiliations

[1 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Anesthesiology, Zhongshan Hospital, , Fudan University, ; Shanghai, China

[2 ]Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China

[3 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Anesthesiology, Shanghai Medical College, , Fudan University, ; Shanghai, China

Author information

Hao Zhang http://orcid.org/0000-0001-5973-7080

Article

Publisher ID: 5656

DOI: 10.1038/s41419-023-05656-9

PMC ID: 9922301

PubMed ID: 36774341

SO-VID: 5c874760-02cd-4380-b49b-0c987227766c

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 28 November 2022

Date revision received : 1 February 2023

Date accepted : 3 February 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: NO.82102253

Award Recipient : Hao Zhang

Funded by: Natural Science Foundation of Shanghai (NO. 21ZR1413400), Shanghai Sailing Program (NO.21YF1406800)

Funded by: the Shanghai Municipal 2021 “Science and Technology Innovation Action Plan” (NO.21JC1401400).

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ScienceOpen disciplines: Cell biology

Keywords: post-translational modifications,infection,immunopathogenesis

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ScienceOpen disciplines: Cell biology

Keywords: post-translational modifications, infection, immunopathogenesis

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Epigenetic mechanisms of Immune remodeling in sepsis: targeting histone modification

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GLUT4 biology

Most cited references 152

Metabolic regulation of gene expression by histone lactylation

Sepsis and septic shock

The language of covalent histone modifications.

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