Endoplasmic Reticulum Stress Amplifies Cytokine Responses in Astrocytes via a PERK/eIF2α/JAK1 Signaling Axis

Area of Science:

• Neuroscience
• Cellular Biology
• Molecular Medicine

Background:

• Neurological disorders involve aberrant cellular processes and signaling pathways.
• Endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and neuroinflammation are key implicated factors.
• ER stress synergizes with TNF-α to amplify inflammatory cytokine production in astrocytes via JAK1.

Purpose of the Study:

• To define the scope and mechanisms of ER stress and TNF-α interaction in inflammatory gene expression.
• To elucidate the signaling axis involving PERK and JAK1 in astrocytes.
• To investigate the role of translational suppression in inflammatory responses.

Main Methods:

• Co-treatment of astrocytes with ER stress inducers and inflammatory cytokines (TNF-α, OSM).
• Assessment of inflammatory gene expression and signaling pathway activation (PERK, eIF2α, JAK1).
• Pharmacological inhibition of integrated stress response (ISR) using ISRIB.
• Analysis of astrocytes with EIF2B5 mutations.

Main Results:

• ER stress and TNF-α cooperatively enhance inflammatory gene expression through a PERK/eIF2α/JAK1 axis.
• PERK-mediated eIF2α phosphorylation suppresses translation of negative regulators (IκBα, SOCS3).
• ISRIB treatment restored negative regulator expression and attenuated inflammatory responses.
• Translational attenuation alone was insufficient to amplify cytokine-induced gene expression in EIF2B5 mutant astrocytes.

Conclusions:

• A novel PERK/eIF2α/JAK1 signaling axis sensitizes astrocytes to inflammatory cytokines.
• This axis provides mechanistic insights into the interplay between ER stress and neuroinflammation.
• Findings highlight the role of translational control in modulating neuroinflammatory responses.