Perfluorooctanoic acid (PFOA) activates astrogliosis-associated neuroinflammation through ER stress-autophagy axis

Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, induces neuroinflammation. However, present understanding regarding its fundamental role in neuroinflammation remains limited. Therefore, in this study, we aimed to clarify the potential association between PFOA and astrocyte activation via the modulation of the endoplasmic reticulum (ER) stress-autophagy axis. The results obtained revealed that PFOA activated astroglia in A-172 astrocytoma cells and primary astrocytes by upregulating the expression levels of autophagy-related proteins (ATG5, BECN1, SQSTM1, and MAP1LC3B-II). It also activated autophagy in A-172 astrocytoma cells and primary astrocytes via the upstream activation of ER stress-related proteins, such as ATF4, GRP78, and CHOP. Further, the pharmacological inhibition of ER stress as well as autophagy prevented PFOA-induced activation of astrogliosis in PFOA-treated A-172 cells and primary astrocytes. We also observed that PFOA-mediated activation of GFAP upregulated the transcription of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6. These findings confirmed the existence of a relationship between ER stress-induced autophagy and astrogliosis in PFOA-treated astrocytes, suggesting that targeting the ER stress-autophagy axis may be a potential therapeutic strategy for reducing PFOA-induced neuroinflammation.