Inflammation and endoplasmic reticulum (ER) stress are associated with many neurological diseases. ER stress is brought on
by the accumulation of misfolded proteins in the ER, which leads to activation of the unfolded protein response (UPR); a conserved
pathway that transmits signals to restore homeostasis or eliminate the irreparably damaged cell. We provide evidence that
inhibition or genetic haploinsufficiency of PKR-like ER kinase (PERK) can selectively control inflammation brought on by ER
stress without impinging on UPR-dependent survival and adaptive responses or normal immune responses. Using astrocytes lacking
one or both alleles of PERK or the PERK inhibitor GSK2606414, we demonstrate that PERK haploinsufficiency or partial inhibition
led to reduced ER stress-induced inflammation (IL-6, CCL2, CCL20 expression) without compromising pro-survival responses.
In contrast, complete loss of PERK blocked canonical PERK-dependent UPR genes and promoted apoptosis. Reversal of eIF2α-mediated
translational repression using ISRIB potently suppressed PERK-dependent inflammatory gene expression. Indicating that the
selective modulation of inflammatory gene expression by PERK inhibition may be linked to attenuation of eIF2α phosphorylation
and reveals a previously unknown link between translational repression and transcription of inflammatory genes. Additionally,
ER stressed astrocytes can drive an inflammatory M1-like phenotype in microglia, and this can be attenuated with inhibition
of PERK. Importantly, targeting PERK neither disrupted normal cytokine signaling in astrocytes or microglia nor impaired macrophage
phagocytosis or T cell polarization. Collectively, this work suggests that targeting PERK may provide a means for selective
immunoregulation in the context of ER stress without disrupting normal immune function.