title: Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses.
abstract: 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 protein kinase R-like endoplasmic reticulum 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, and CCL20 expression) without compromising prosurvival 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.
authors.affiliation: From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26505 and.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Guthrie
authors.affiliation: the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Abiraman
authors.affiliation: From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26505 and.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Plyler
authors.affiliation: From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26505 and.
authors.forename: Neil T
authors.initials: NT
authors.lastname: Sprenkle
authors.affiliation: the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Gibson
authors.affiliation: the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Braden C
authors.initials: BC
authors.lastname: McFarland
authors.affiliation: the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Rajani
authors.initials: R
authors.lastname: Rajbhandari
authors.affiliation: the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Rowse
authors.affiliation: the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
authors.affiliation: From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26505 and gpmeares@hsc.wvu.edu.
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Meares
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000276:immunology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000276:immunology; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D000225:Adenine; D015852:Eukaryotic Initiation Factor-2; D007211:Indoles; D019892:eIF-2 Kinase; C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
keywords: astrocyte; chemokine; cytokine; microglia; unfolded protein response (UPR)