title: PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation.
abstract: Neuroinflammation and endoplasmic reticulum (ER) stress are associated with many neurological diseases. Here, we have examined the interaction between ER stress and JAK/STAT-dependent inflammation in glial cells. We show that ER stress is present in the central nervous system (CNS) concomitant with inflammation and astrogliosis in the multiple sclerosis (MS) mouse model of experimental autoimmune encephalomyelitis (EAE). Astrocytes do not easily succumb to ER stress but rather activate an inflammatory program involving activation of STAT3 in a JAK1-dependent fashion. ER stress-induced activation of the JAK1/STAT3 axis leads to expression of interleukin 6 (IL-6) and several chemokines. Moreover, the activation of STAT3 signaling is dependent on PERK, a central component of the ER stress response, which we show is phosphorylated by JAK1. Disruption of PERK abrogates ER stress-induced activation of STAT3 and subsequent gene expression. Additionally, ER-stressed astrocytes, via paracrine signaling, can stimulate activation of microglia, leading to production of IL-6 and oncostatin M (OSM). These IL-6 cytokines can then synergize with ER stress in astrocytes to drive inflammation. Together, this work describes a new PERK/JAK1/STAT3 signaling pathway that elicits a feed-forward inflammatory loop involving astrocytes and microglia to drive neuroinflammation, which may be relevant in diseases such as MS.
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA mearegp@uab.edu.
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Meares
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Rajani
authors.initials: R
authors.lastname: Rajbhandari
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Nozell
authors.affiliation: Department of Surgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Mobley
authors.affiliation: The Medical College of Wisconsin, Department of Biochemistry, Milwaukee, Wisconsin, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000502:physiology; D002450:Cell Communication; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D025461:Feedback, Physiological; D007249:Inflammation / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D053613:Janus Kinase 1; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D019892:eIF-2 Kinase; C494087:Stat3 protein, mouse; C507905:Jak1 protein, mouse
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