Atmospheric particulate matter aggravates CNS demyelination through involvement of TLR-4/NF-kB signaling and microglial activation
- Shaanxi Normal University, China
- First Affiliated Hospital of Zhengzhou University, China
- 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.
Article and author information
Author details
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).
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.
Metrics
-
- 1,193
- views
-
- 195
- downloads
-
- 22
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.
-
- Immunology and Inflammation
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.
