Potentiated fractalkine signaling axis affects neuroinflammation in 1,2-dichloroethane- intoxicated mice via divergent modulating ways on microglial hyperactivation.

1,2-Dichloroethane (1,2-DCE), a synthetic halohydrocarbon, can cause toxic encephalopathy in workers exposed to it as an industrial solvent. Crosstalk between astrocytes and microglia with proinflammatory phenotype triggered and amplified neuroinflammation, leading to brain edema in 1,2-DCE intoxicated mice. Chemokine fractalkine (FKN) affects neuroinflammation via regulating microglial activation during the course of brain disorders. However, roles of FKN signaling axis in 1,2-DCE-induced neuroinflammation remains unknown. In this study, roles and possible mechanisms of FKN signaling axis on microglial hyperactivation and neuroinflammation were investigated by constructing the mouse model of 1,2-DCE intoxication. We found that FKN signaling axis in the brains was potentiated at early stage of intoxication, but suppressed at late stage. FKN signaling axis potentiated by overexpressing FKN and CX3CR1 or treatment with low dose sFKN alleviated pro-inflammatory polarization, and enhanced anti-inflammatory polarization of microglia, thereby attenuated neuroinflammation. Besides, overexpressing FKN and CX3CR1 also alleviated astrocytic hyperactivation. Contrastly, treatment with high dose sFKN failed to attenuate proinflammatory polarization, whereas suppressed anti-inflammatory polarization of microglia, thereby enhanced neuroinflammation. Further in vitro experiments revealed that exposure to 2-CE (a metabolite of 1,2-DCE in vivo) disrupted the homeostasis of adenosine receptor expression in microglia, resulting in the downregulation of A1R and the upregulation of A2aR. This disruption caused the pro-inflammatory activation of microglia and subsequent neuroinflammatory responses through excessive activation of the A2aR mediated adenosine signaling pathway. Collectively, FKN signaling axis plays divergent roles on the activation of microglial hyperactivation and neuroinflammation in 1,2-DCE intoxicated mice, which may be linked to its distinct impacts on the expression of A1R and A2aR in microglia.