Publication Date

2014-12-09

Availability

Embargoed

Embargo Period

2016-12-08

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2014-07-17

First Committee Member

Abigail Hackam

Second Committee Member

Victor Perez

Third Committee Member

Zhibin Chen

Fourth Committee Member

Enrique Mesri

Fifth Committee Member

Alan Pollack

Abstract

Oxidative-stress is key in the pathogenesis of several diseases and the general aging process. Molecular targets of oxidative stress include nucleic acids, proteins, and lipids. It has previously been established that a particular lipid peroxidation product, carboxyethylpyrrole (CEP), accumulates in melanoma, autistic brain tissue, atherosclerotic plaques, sites undergoing wound healing, and in the retinas of AMD patients. The role of CEP is best characterized in AMD and in addition to the retina, elevated levels of CEP and autoantibodies against CEP are found in the sera of AMD patients (versus age-matched controls). Our previous studies have demonstrated CEP as a potential molecular link between oxidative damage, inflammation, and immunity; such that immunization of mice with CEP-adducts leads to AMD-like lesions, anti-CEP antibody production, and localized infiltration of macrophages. Retinal infiltrating macrophages are a feature of human AMD pathology as well. Given the coincident accumulation of CEP and macrophages in both human AMD pathology and in our AMD mouse model of AMD, we investigated the ability of CEP-adducts to activate innate immune signaling in macrophages. We found that CEP-adducts cannot induce inflammatory cytokine production by themselves, but instead synergizes with low-dose TLR2-agonists and not agonists for other TLRs. Regarding TLR2, we observed that CEP-adducts selectively potentiate TLR2/TLR1-signaling (and not TLR2/TLR6-signaling). Furthermore, CEP-adducts have previously been implicated as TLR2-ligands themselves, but we found that TLR2 is not sufficient for propagating CEP-signaling. These studies uncover a novel synergistic inflammatory relationship between an endogenously produced oxidation molecule and a pathogen-derived product. This discovery has implications in the AMD disease process and other oxidative-stress driven pathologies that exhibit the coincident accumulation of CEP-adducts and macrophages (i.e., atherosclerosis, cancer).

Keywords

oxidative stress; oxidized lipid; innate immunity; toll-like receptor

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