| RRC ID |
86928
|
| Author |
Lahiri A, Sims SG, Herstine JA, Meyer A, Marshall MJ, Jahan I, Adhicary S, Bradbury AM, Meares GP.
|
| Title |
Endoplasmic Reticulum Stress Amplifies Cytokine Responses in Astrocytes via a PERK/eIF2α/JAK1 Signaling Axis.
|
| Journal |
Glia
|
| Abstract |
Aberrant activation of multiple cellular processes and signaling pathways is a hallmark of many neurological disorders. Understanding how these processes interact is crucial for elucidating the neuropathogenesis of these diseases. Among these, endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and neuroinflammation are frequently implicated. Previously, we demonstrated that ER stress synergizes with tumor necrosis factor (TNF)-α to amplify interleukin (IL)-6 and C-C motif chemokine ligand (CCL)20 production in astrocytes through a Janus kinase 1 (JAK1)-dependent mechanism. Here, we expand on this finding by defining the scope and underlying mechanisms of this phenomenon. We show that ER stress and TNF-α cooperatively enhance inflammatory gene expression in astrocytes via a signaling axis that requires both protein kinase R (PKR)-like ER kinase (PERK) and JAK1. PERK-mediated phosphorylation of eukaryotic translation initiation factor (eIF)2α suppresses protein translation, delaying the expression of negative regulators such as NF-κB inhibitor (IκB)α and suppressor of cytokine signaling (SOCS)3 following TNF-α or oncostatin M (OSM) stimulation, respectively. Pharmacological reversal of p-eIF2α-dependent translational suppression using the small molecule integrated stress response inhibitor (ISRIB) restored IκBα and SOCS3 expression and attenuated the ER stress-induced enhancement of TNF-α- or OSM-driven inflammatory responses. Notably, astrocytes harboring a vanishing white matter-associated EIF2B5 mutation revealed that translational attenuation alone is insufficient to amplify cytokine-induced gene expression. Together, these findings identify a PERK/eIF2α/JAK1 signaling axis that sensitizes astrocytes to inflammatory cytokines, providing new mechanistic insights into the interactions between ER stress and neuroinflammation.
|
| Volume |
73(11)
|
| Pages |
2273-2288
|
| Published |
2025-11-1
|
| DOI |
10.1002/glia.70067
|
| PMID |
40685560
|
| PMC |
PMC12436993
|
| MeSH |
Animals
Astrocytes* / drug effects
Astrocytes* / metabolism
Cells, Cultured
Cytokines* / metabolism
Endoplasmic Reticulum Stress* / drug effects
Endoplasmic Reticulum Stress* / physiology
Eukaryotic Initiation Factor-2* / metabolism
Janus Kinase 1* / metabolism
Mice
Mice, Inbred C57BL
Signal Transduction* / drug effects
Signal Transduction* / physiology
eIF-2 Kinase* / genetics
eIF-2 Kinase* / metabolism
|
| IF |
5.984
|
| Resource |
| Mice |
RBRC10057 |
