Perfluorooctane sulfonate mediates microglial activation and secretion of TNF-α through Ca2 +-dependent PKC-NF-кB signaling

• PFOS exposure induced TNF-α secretion in HAPI microglia.
• NF-κB p65 and PKC were activated by PFOS in HAPI microglia.
• [Ca2 +]i was elevated following PFOS exposure in HAPI microglia.
• TNF-α secreted by HAPI microglia participated in the apoptosis of SH-SY5Y cells.

Perfluorooctane sulfonate (PFOS), a ubiquitous pollutant widely found in the environment and biota, can cause numerous adverse effects on human health. In recent years, PFOS's toxic effects on the central nervous system (CNS) have been shown. However, we still have a lot to study in the underlying molecular mechanism of PFOS's neurotoxicity. Microglia, the innate immune cells of CNS, are critically implicated in various neurological diseases caused by pro-inflammatory mediators. In our research, we found that HAPI microglia secreted tumor necrosis factor-alpha (TNF-α) after PFOS exposure in time-dependent and dose-dependent way. We also discovered that intracellular concentration of free Ca2 + ([Ca2 +]i) significantly increased after PFOS treatments. It was noteworthy here the secretion of TNF-α mediated by PFOS was blocked by Ca2 + inhibitor and protein kinase C (PKC) inhibitor. Besides these, we had learned as well that PFOS brought about the up-regulation of phosphorylated nuclear factor kappa B (NF-кB) p65 expression and accelerated degradation of NF-κB inhibitor alpha (IкBα), however, these effects could be attenuated or blocked by Ca2 + inhibitor and PKC inhibitor. Finally, through treating SH-SY5Y cells with PFOS-treated microglial conditioned medium, we demonstrated that TNF-α mediated neuronal apoptosis. To sum up, our research had shown, for the first time, that the distinct TNF-α secretion brought by PFOS in HAPI microglia, was achieved through the Ca2 +-dependent PKC-NF-кB signaling, subsequently participating in neuronal loss.