Virginia Tech
Super Low Dose Endotoxin Exacerbates Low Grade Inflammation through Modulating Cell Stress and Decreasing Cellular Homeostatic Protein Expression
Abstract
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.
Degree
thesis:*- Name thesis:degree_name
- Ph. D.
- Level thesis:degree_level
- doctoral
- Discipline thesis:degree_discipline
- Biological Sciences
- Department dc:contributor.department
- Biological Sciences
- Grantor dc:publisher
- Virginia Tech
- Year dc:date.issued
- 2017
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Lyle, Chimera
- Chair dc:contributor.committeechair
-
- Li, Liwu
- Committee members dc:contributor.committeemember
-
- Bevan, David R.
- Lawrence, Christopher B.
- Yuan, Lijuan
Subjects
dc:subject × 8Rights
dc:rights- Statement dc:rights
-
- In Copyright
- Licence dc:rights.uri
Identifiers
dc:identifier.*- Dc Identifier Other
- vt_gsexam:11275
- OAI identifier oai:identifier
- oai:vtechworks.lib.vt.edu:10919/86360