Super Low Dose Endotoxin Exacerbates Low Grade Inflammation through Modulating Cell Stress and Decreasing Cellular Homeostatic Protein Expression

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dc.contributor.authorLyle, Chimeraen
dc.contributor.committeechairLi, Liwuen
dc.contributor.committeememberBevan, David R.en
dc.contributor.committeememberLawrence, Christopher B.en
dc.contributor.committeememberYuan, Lijuanen
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2018-12-13T07:00:50Zen
dc.date.available2018-12-13T07:00:50Zen
dc.date.issued2017-06-20en
dc.description.abstractThe establishment of non-resolving inflammation underlies the pathogenesis of chronic inflammatory diseases in humans. Super low dose (SLD) endotoxin has been associated with exacerbating inflammation and the pathogenesis of chronic inflammatory diseases. However, the underlying molecular mechanisms are not well studied. In this study, I tested the hypothesis that SLD endotoxin may potentiate non-resolving innate immune cell inflammation through disrupting cellular endoplasmic reticulum (ER) homeostasis. We chose to study the dynamics of ER homeostasis in macrophages stimulated with SLD endotoxin. In naïve cells, ER stressor such as tunicamycin (TM) not only will induce cellular stress and inflammation through JNK and NFkβ activation, but also will cause subsequent compensatory homeostasis through inducing homeostatic molecules such as XBP1 and GRP78/BiP. We observed that cells challenged with SLD endotoxin have significantly reduced expression of homeostatic molecules XBP1 and BiP. Mechanistically, we observed that SLD-LPS increases phosphorylated HCK expression in TM treated cells. Phosphorylated HCK activation resulted in the phosphorylation of Golgi protein GRASP, leading to unstacking of Golgi cisterna and overall dysfunction of the Golgi apparatus. Dysfunctional Golgi apparatus and its effect on protein transport and secretion, may account for decreased levels of Site 2 Protease, reduced generation of ATF6 and its transcriptional target BiP. Taken together, our study reveal that super low dose endotoxin exacerbates low grade inflammation through increasing phosphorylation of HCK, inducing Golgi dysfunction, and decreasing BiP /homeostatic protein expression in innate immune cells.en
dc.description.degreePh. D.en
dc.format.mediumETDen
dc.identifier.othervt_gsexam:11275en
dc.identifier.urihttp://hdl.handle.net/10919/86360en
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectInnate Immunityen
dc.subjectBiPen
dc.subjectLPSen
dc.subjectChaperone Proteinen
dc.subjectEndoplasmic Reticulumen
dc.subjectUPRen
dc.subjectATF6en
dc.subjectMacrophageen
dc.titleSuper Low Dose Endotoxin Exacerbates Low Grade Inflammation through Modulating Cell Stress and Decreasing Cellular Homeostatic Protein Expressionen
dc.typeDissertationen
thesis.degree.disciplineBiological Sciencesen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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