title: Deregulated unfolded protein response in chronic wounds of diabetic ob/ob mice: a potential connection to inflammatory and angiogenic disorders in diabetes-impaired wound healing.
abstract: Type-2 diabetes mellitus (T2D) represents an important metabolic disorder, firmly connected to obesity and low level of chronic inflammation caused by deregulation of fat metabolism. The convergence of chronic inflammatory signals and nutrient overloading at the endoplasmic reticulum (ER) leads to activation of ER-specific stress responses, the unfolded protein response (UPR). As obesity and T2D are often associated with impaired wound healing, we investigated the role of UPR in the pathologic of diabetic-impaired cutaneuos wound healing. We determined the expression patterns of the three UPR branches during normal and diabetes-impaired skin repair. In healthy and diabetic mice, injury led to a strong induction of BiP (BiP/Grp78), C/EBP homologous protein (CHOP) and splicing of X-box-binding protein (XBP)1. Diabetic-impaired wounds showed gross and sustained induction of UPR associated with increased expression of the pro-inflammatory chemokine macrophage inflammatory protein (MIP)2 as compared to normal healing wounds. In vitro, treatment of RAW264.7 macrophages with tunicamycin, and subsequently stimulation with lipopolysaccharide (LPS) and interferon (IFN)-γ enhances MIP2 mRNA und protein expression compared to proinflammatory stimulation alone. However, LPS/IFNγ induced vascular endothelial growth factor (VEGF) production was blunted by tunicamycin induced-ER stress. Hence, UPR is activated following skin injury, and functionally connected to the production of proinflammatory mediators. In addition, prolongation of UPR in diabetic non-healing wounds aggravates ER stress and weakens the angiogenic phenotype of wound macrophages.
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. Electronic address: Schuermann@med.uni-frankfurt.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schürmann
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Itamar
authors.initials: I
authors.lastname: Goren
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linke
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications* / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014157:Transcription Factors / Q000235:genetics; D056811:Unfolded Protein Response; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*; D000071717:X-Box Binding Protein 1
chemical_list: D042501:Angiogenic Proteins; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C467480:vascular endothelial growth factor A, mouse; D051742:Transcription Factor CHOP
keywords: Chronic wounds; Diabetes mellitus; ER stress; Unfolded protein response; Wound healing