Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress

Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice...

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Main Authors: Huanghui Wu, Han Bao, Cong Liu, Qiao Zhang, Ailing Huang, Minxue Quan, Chunhui Li, Ying Xiong, Guozhong Chen, Lichao Hou
Format: Article
Language:English
Published: Frontiers Media S.A. 2022-06-01
Series:Frontiers in Immunology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2022.854202/full
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author Huanghui Wu
Han Bao
Cong Liu
Qiao Zhang
Ailing Huang
Minxue Quan
Chunhui Li
Ying Xiong
Guozhong Chen
Lichao Hou
author_facet Huanghui Wu
Han Bao
Cong Liu
Qiao Zhang
Ailing Huang
Minxue Quan
Chunhui Li
Ying Xiong
Guozhong Chen
Lichao Hou
author_sort Huanghui Wu
collection DOAJ
description Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice with chronic stress. C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) and corticosterone drinking, respectively, for 4 weeks. Negative emotional behaviors were comprehensively investigated. Microglial morphology, oxidative stress, and inflammation, as well as C-type lectin receptor 2D (Clec2d) and Toll-like receptor 9 (TLR9) expression in medial prefrontal cortex (mPFC) were assessed with flow cytometer and cell sorting. Specifically, microglial pro-inflammatory activation and inflammation were further investigated with stereotactic injection of recombinant nucleosomes and histones in mPFC and further evaluated with AAV-Clec2d knocking-down, DNase I, and activated protein C (APC) pretreatment. Moreover, the rescue effect by AAV-Clec2d knocking-down was observed in mice with chronic stress. Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors and accompanied with significant microglial oxidative stress and inflammation, indicating by reactive oxygen species (ROS) production, primed nuclear factor-κB (NF-κB) signaling pathway, activated NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome, and upregulated Clec2d and TLR9 in mPFC, together with histones dictation in cerebrospinal fluid and extracellular trap formation. Stereotactic injection of nucleosomes was contributed to promote microglial inflammation rather than histones in mPFC, indicating that the pro-inflammatory role was derived from extracellular histones-bound DNA but not freely histones. AAV-Clec2d knocking-down, DNase I, and APC were all effective to inhibit nucleosome-induced microglial oxidative stress and inflammation. Moreover, AAV-Clec2d knocking-down in mice with chronic stress exhibited reduced microglial inflammation and improved negative emotional behaviors. Our findings reveal a novel mechanism of DAMP-associated inflammation that extracellular nucleosomes accelerate microglial inflammation via Clec2d and TLR9, and then contribute to chronic stress-induced emotional disorders.
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spelling doaj.art-b205ede03a2041aa926c45ffef3534412022-12-22T00:33:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.854202854202Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic StressHuanghui Wu0Han Bao1Cong Liu2Qiao Zhang3Ailing Huang4Minxue Quan5Chunhui Li6Ying Xiong7Guozhong Chen8Lichao Hou9Department of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital Affiliated to Tongji University, Shanghai, ChinaDepartment of Anesthesiology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDamage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice with chronic stress. C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) and corticosterone drinking, respectively, for 4 weeks. Negative emotional behaviors were comprehensively investigated. Microglial morphology, oxidative stress, and inflammation, as well as C-type lectin receptor 2D (Clec2d) and Toll-like receptor 9 (TLR9) expression in medial prefrontal cortex (mPFC) were assessed with flow cytometer and cell sorting. Specifically, microglial pro-inflammatory activation and inflammation were further investigated with stereotactic injection of recombinant nucleosomes and histones in mPFC and further evaluated with AAV-Clec2d knocking-down, DNase I, and activated protein C (APC) pretreatment. Moreover, the rescue effect by AAV-Clec2d knocking-down was observed in mice with chronic stress. Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors and accompanied with significant microglial oxidative stress and inflammation, indicating by reactive oxygen species (ROS) production, primed nuclear factor-κB (NF-κB) signaling pathway, activated NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome, and upregulated Clec2d and TLR9 in mPFC, together with histones dictation in cerebrospinal fluid and extracellular trap formation. Stereotactic injection of nucleosomes was contributed to promote microglial inflammation rather than histones in mPFC, indicating that the pro-inflammatory role was derived from extracellular histones-bound DNA but not freely histones. AAV-Clec2d knocking-down, DNase I, and APC were all effective to inhibit nucleosome-induced microglial oxidative stress and inflammation. Moreover, AAV-Clec2d knocking-down in mice with chronic stress exhibited reduced microglial inflammation and improved negative emotional behaviors. Our findings reveal a novel mechanism of DAMP-associated inflammation that extracellular nucleosomes accelerate microglial inflammation via Clec2d and TLR9, and then contribute to chronic stress-induced emotional disorders.https://www.frontiersin.org/articles/10.3389/fimmu.2022.854202/fullextracellular nucleosomesmicrogliaC-type lectin receptor 2Dtoll-like receptor 9inflammationchronic stress
spellingShingle Huanghui Wu
Han Bao
Cong Liu
Qiao Zhang
Ailing Huang
Minxue Quan
Chunhui Li
Ying Xiong
Guozhong Chen
Lichao Hou
Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress
Frontiers in Immunology
extracellular nucleosomes
microglia
C-type lectin receptor 2D
toll-like receptor 9
inflammation
chronic stress
title Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress
title_full Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress
title_fullStr Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress
title_full_unstemmed Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress
title_short Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress
title_sort extracellular nucleosomes accelerate microglial inflammation via c type lectin receptor 2d and toll like receptor 9 in mpfc of mice with chronic stress
topic extracellular nucleosomes
microglia
C-type lectin receptor 2D
toll-like receptor 9
inflammation
chronic stress
url https://www.frontiersin.org/articles/10.3389/fimmu.2022.854202/full
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