title: PERK and XBP1 differentially regulate CXCL10 and CCL2 production.
abstract: Inflammation plays a key role in the pathogenesis of many retinal degenerative diseases related with photoreceptor dysfunction/degeneration. However the involvement of photoreceptor cells in inflammatory reactions is largely unknown as they are not considered as inflammatory cells. In this study, we assessed whether photoreceptor cells can produce CCL2 and CXCL10, two important players in inflammation during endoplasmic reticulum (ER) stress. After photoreceptor 661 W cells were treated with ER stress inducer thapsigargin (TG), induction of ER stress increased CXCL10 and CCL2 expression at both mRNA and protein levels, which was significantly blocked by an ER stress blocker 4-phenylbutyrate. ER stress contains three pathways: PERK, ATF6 and IRE1α. Knockdown of PERK attenuated TG-induced CXCL10 and CCL2 mRNA expression, associated with significant decreases in phosphorylation of NF-κB RelA and STAT3. In contrast to PERK, knockdown of XBP1, which is activated by IRE1α-mediated splicing, robustly enhanced TG-induced CXCL10 and CCL2 expression and phosphorylation of NF-κB RelA and STAT3. Blockade of NF-κB or STAT3 markedly diminished TG-induced CXCL10 and CCL2 expression. The specific roles of PERK and XBP1 in CXCL10 and CCL2 expression were further investigated by treating photoreceptor cells with advanced glycation end products (AGE) and high glucose (HG), two of the major contributors to diabetic complications. Similarly, AGE and HG induced CXCL10 and CCL2 expression in which PERK was a positive regulator while XBP1 was a negative regulator. These studies suggest that photoreceptors may be involved in retinal inflammation by expressing chemokines CXCL10 and CCL2. PERK and IRE1α/XBP1 in the unfolded protein response differentially regulate the expression of CXCL10 and CCL2 likely through modulation of ER stress-induced NF-κB RelA and STAT3 activation.
authors.affiliation: Research Center for Neurology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Center for Biomedical Engineering, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Sha
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
authors.affiliation: Research Center for Neurology, Xuzhou Medical University, Xuzhou, Jiangsu, China. Electronic address: gds@xzmc.edu.cn.
authors.forename: Dian-Shuai
authors.initials: DS
authors.lastname: Gao
authors.affiliation: Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX, USA; Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, TX, USA. Electronic address: we2zhang@utmb.edu.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics*; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics*; D016207:Cytokines; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D016207:Cytokines; D012313:RNA; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C491768:Ccl2 protein, mouse; C485433:Cxcl10 protein, mouse; C000605544:Xbp1 protein, mouse
keywords: Chemokine; ER stress; NF-κB; Photoreceptor; STAT3