Atmospheric particulate matter aggravates CNS demyelination via TLR-4/NF-κB-mediated microglia pathogenic activities

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-{kappa}B 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. SignificanceAn atmospheric trigger, the respirable particulate matter boost microglia pathogenic activities in the context of CNS demyelination by activating TLR-4/NF-{kappa}B signaling axis in animal models of immune- and toxicity-induced demyelination, as well as myelinogenesis during postnatal development.