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  1. Evaluation Summary:

    The authors investigated Atmospheric Particulate Matter (PM) , a mimetic of current air pollution and how it affects myelination in the central nervous system (CNS) using an animal model of demyelination. They showed that the PM caused changes in myelination that associated with microglial activation and markers of inflammation. In vitro modeling indicates PM can activate microglial via the TLR4/NFkB signaling pathway.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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  2. Reviewer #1 (Public Review):

    This is a manuscript by Han et al. to describe their findings that atmospheric particulate matter, one of the leading environmental risk factors for the global burden of disease, aggravates CNS demyelination via TLR-4/NF-κB-mediated microglia pathogenic activities. 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. TLR-4/NF-κB signaling mediated a core network of genes that control PM-triggered microglia pathogenicity. This study is interesting and novel, and the manuscript is well written.

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  3. Reviewer #2 (Public Review):

    The present work by Han et al. demonstrates that PM exposure aggravates neuroinflammation, myelin damage, and motor coordination ability dysfunction by promoting microglial proinflammatory activity. In addition, the authors showed that PM exposure enhances microglial pathogenic activity by activating the TLR-4/NF-κB signaling axis. These data supply the direct testimony of PM-triggered demyelinating disorders, and establishes a systematic approach for studying the effects of environmental exposure on neurological diseases. This work is an interesting and complete research, and the paper is well designed and written. However, the manuscript raises the following concerns that need to be addressed:

    Major comments:

    1. In Fig 1, the authors showed that for both central and peripheral immunity, the percentages of Th17 (CD4+ IL17+) and Th1 (CD4+ IFN-γ+) cells were significantly increased under PM exposure. PM has already been reported to have some effects on peripheral immunity. The authors remain to examine the effects of PM on different T cells subsets in vitro?

    2. In both Fig 2 and Fig 3, the authors show the activation of microglia and astrocytes by PM. Although in Figure 1, the authors mentioned that activated IBA1+ microglia and A2B5+ OPCs accumulated significantly in demyelinated injured areas in PM-treated mice, while PM inhalation had no significant effect on GFAP+ astrocytes. Microglia showed activation results by PM in three complementary animal models, which led the authors to select the final follow-up study subjects of microglia. Given the above results, the authors should examine the direct effects of PM on primary astrocytes, at least in vitro.

    3. In Fig 4. The authors proposed that treatment of purified primary OPC with microglia-conditioned medium (MCM) in vitro prevented OPC differentiation. OPC are essential for remyelination after central nervous system injury. Therefore, it is necessary for the authors to investigate the direct effects of PM on OPC and thus better illustrate the effects of PM exposure on CNS demyelinating diseases.

    4. In Fig 5. The authors predicted targeted genes for PM to induce microglial activation via the TLR-4/NF-κB signaling axis by RNA-seq and ChIP-seq. However, the manuscript would benefit if the authors also discussed the role of predicted target genes in PM-induced microglial activation, and what might be done subsequently.

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