Atmospheric particulate matter aggravates CNS demyelination through involvement of TLR-4/NF-kB signaling and microglial activation

  1. Bing Han
  2. Xing Li
  3. Ruo-Song Ai
  4. Si-Ying Deng
  5. Ze-Qing Ye
  6. Xin Deng
  7. Wen Ma
  8. Shun Xiao
  9. Jing-Zhi Wang
  10. Li-Mei Wang
  11. Chong Xie
  12. Yan Zhang
  13. Yan Xu
  14. Yuan Zhang  Is a corresponding author
  1. Shaanxi Normal University, China
  2. First Affiliated Hospital of Zhengzhou University, China
  3. Shanghai Jiaotong University School of Medicine, China

Abstract

Atmospheric Particulate Matter (PM) is one of the leading environmental risk factors for the global burden of disease. Increasing epidemiological studies demonstrated that PM plays a significant role in CNS demyelinating disorders; however, there is no direct testimony of this, and yet the molecular mechanism by which the occurrence remains unclear. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that PM exposure aggravates neuroinflammation, myelin injury, and dysfunction of movement coordination ability via boosting microglial pro-inflammatory activities, in both the pathological demyelination and physiological myelinogenesis animal models. Indeed, pharmacological disturbance combined with RNA-seq and ChIP-seq suggests that TLR-4/NF-kB signaling mediated a core network of genes that control PM-triggered microglia pathogenicity. In summary, our study defines a novel atmospheric environmental mechanism that mediates PM-aggravated microglia pathogenic activities, and establishes a systematic approach for the investigation of the effects of environmental exposure in neurologic disorders.

Data availability

Figure 1 - Source Data 1, Figure 2 - Source Data 1, Figure 3 - Source Data 1, Figure 3 - Source Data 1, Figure supplement 1 - Source Data 1 and Figure supplement 2 - Source Data 1 contain the numerical data used to generate the figures. Sequencing data are available through the NCBI Gene Expression Omnibus GSE183099.

The following data sets were generated

Article and author information

Author details

  1. Bing Han

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Xing Li

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Ruo-Song Ai

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Si-Ying Deng

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Ze-Qing Ye

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Xin Deng

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Wen Ma

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Shun Xiao

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Jing-Zhi Wang

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Li-Mei Wang

    First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Chong Xie

    Shanghai Jiaotong University School of Medicine, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Yan Zhang

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Yan Xu

    Shaanxi Normal University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Yuan Zhang

    Shaanxi Normal University, Xi'an, China
    For correspondence
    yuanzhang_bio@126.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2463-4599

Funding

National Natural Science Foundation of China (82071396)

  • Yuan Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental procedures and protocols of mice were approved by the Committee on the Ethics of Animal Experiments of Shaanxi Normal University (No. ECES-2015-0247) and were carried out in accordance with the approved institutional guidelines and regulations. C57BL/6 mice (8-10 weeks of age) were purchased from the Fourth Military University (Xi'an, China).

Reviewing Editor

  1. Brandon K Harvey, NIDA/NIH, United States

Publication history

  1. Received: July 16, 2021
  2. Preprint posted: August 10, 2021 (view preprint)
  3. Accepted: February 18, 2022
  4. Accepted Manuscript published: February 24, 2022 (version 1)
  5. Version of Record published: March 3, 2022 (version 2)
  6. Version of Record updated: March 15, 2022 (version 3)

Copyright

© 2022, Han et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Bing Han
  2. Xing Li
  3. Ruo-Song Ai
  4. Si-Ying Deng
  5. Ze-Qing Ye
  6. Xin Deng
  7. Wen Ma
  8. Shun Xiao
  9. Jing-Zhi Wang
  10. Li-Mei Wang
  11. Chong Xie
  12. Yan Zhang
  13. Yan Xu
  14. Yuan Zhang
(2022)
Atmospheric particulate matter aggravates CNS demyelination through involvement of TLR-4/NF-kB signaling and microglial activation
eLife 11:e72247.
https://doi.org/10.7554/eLife.72247

Further reading

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    The combined impact of immunity and SARS-CoV-2 variants on viral kinetics during infections has been unclear.

    Methods:

    We characterized 1,280 infections from the National Basketball Association occupational health cohort identified between June 2020 and January 2022 using serial RT-qPCR testing. Logistic regression and semi-mechanistic viral RNA kinetics models were used to quantify the effect of age, variant, symptom status, infection history, vaccination status and antibody titer to the founder SARS-CoV-2 strain on the duration of potential infectiousness and overall viral kinetics. The frequency of viral rebounds was quantified under multiple cycle threshold (Ct) value-based definitions.

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    Among individuals detected partway through their infection, 51.0% (95% credible interval [CrI]: 48.3–53.6%) remained potentially infectious (Ct <30) 5 days post detection, with small differences across variants and vaccination status. Only seven viral rebounds (0.7%; N=999) were observed, with rebound defined as 3+days with Ct <30 following an initial clearance of 3+days with Ct ≥30. High antibody titers against the founder SARS-CoV-2 strain predicted lower peak viral loads and shorter durations of infection. Among Omicron BA.1 infections, boosted individuals had lower pre-booster antibody titers and longer clearance times than non-boosted individuals.

    Conclusions:

    SARS-CoV-2 viral kinetics are partly determined by immunity and variant but dominated by individual-level variation. Since booster vaccination protects against infection, longer clearance times for BA.1-infected, boosted individuals may reflect a less effective immune response, more common in older individuals, that increases infection risk and reduces viral RNA clearance rate. The shifting landscape of viral kinetics underscores the need for continued monitoring to optimize isolation policies and to contextualize the health impacts of therapeutics and vaccines.

    Funding:

    Supported in part by CDC contract #200-2016-91779, a sponsored research agreement to Yale University from the National Basketball Association contract #21-003529, and the National Basketball Players Association.

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