Dissertation
25-Hydroxycholesterol Regulates Inflammation by Activating Integrin-FAK Signaling Pathway
Washington State University
Doctor of Philosophy (PhD), Washington State University
2020
DOI:
https://doi.org/10.7273/000005521
Abstract
Inflammation is part of host innate immune response constituting the first line of defense against invading pathogens. Regulated inflammation is required for tissue homeostasis and host defense however, dysregulated inflammation is detrimental as it leads to tissue damage and development of various inflammatory diseases like arthritis, diabetes, Alzheimer’s etc. The cells of innate immune system like macrophages play a pivotal role during inflammation. Various receptors like Pathogen Recognition Receptors (PRRs) and Tumor Necrosis Factor-α receptor (TNFR) play important roles in triggering inflammatory response during infectious and non-infectious diseases. The activation of PRRs and TNFR results in the activation of various downstream signaling cascade which includes NFB, MAPK (mitogen activated protein kinase) and type I interferon pathways. Specifically, activation of NFB ad MAPK pathways results in the trans-activation of pro-inflammatory genes and subsequent production of pro-inflammatory cytokines and chemokines that shapes the innate immune inflammatory response. Our study has identified a lipid oxysterol 25 hydroxycholesterol (25HC) as a key positive regulator of PRR and TNFR mediated inflammatory response. 25HC is generated from the enzymatic conversion of cholesterol to 25HC by cholesterol 25-hydroxylase (C25H). Here, in we report that expression of C25H and extracellular production of 25HC from a cytosolic PRR nucleotide oligomerization domain protein 2 (Nod2) activated cells, TNFR activated cells and virus (Respiratory syncytial virus and influenza virus) infected macrophages. During these events, extracellular 25HC binds to cell surface integrin to activate integrin- FAK (focal adhesion kinase)-NFB signaling pathway for optimal pro-inflammatory response. Furthermore, our study also reveals that C25H expression in TNFR activated cells require NFB and MAPK pathways. Thus, our study has identified MAPK/NFB-C25H-25HC-integrin-FAK-NFB signaling network as a novel cellular mechanism involved in amplification of the pro-inflammatory response following Nod2 (PRR) and TNFR activation. Furthermore, we showed that a lipid oxysterol like 25HC can act as a “bridge” to link PRR and TNFR pathways with integrin-FAK signaling for optimal pro-inflammatory response.
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Details
- Title
- 25-Hydroxycholesterol Regulates Inflammation by Activating Integrin-FAK Signaling Pathway
- Creators
- Swechha Mainali Pokharel
- Contributors
- Santanu Bose (Advisor)Anthony V Nicola (Committee Member)Troy Bankhead (Committee Member)Tanya Miura (Committee Member) - University of Idaho
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 143
- Identifiers
- 99901052140401842
- Language
- English
- Resource Type
- Dissertation