Year of Award

2016

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Elizabeth Putnam

Commitee Members

Andrij Holian, Keven Roberts, Christopher Migliaccio, John Hoidal

Abstract

Exposure to bioactive environmental particles and engineered nanoparticles are a significant public health concern. Inhalation of bioactive particles can result in chronic inflammation, which drives tissue remodeling and fibrosis. Furthermore, chronic inflammation can increase individual susceptibility to other diseases including cancer and autoimmune diseases. The macrophage is the critical cell in particle clearance following exposure, and is central to the inflammatory responses and tissue remodeling. Phagocytosed bioactive particles within macrophages cause cytotoxicity and activation of the NLRP3 inflammasome, outcomes that are both essential to inflammation and disease development. However, mechanisms that regulate NLRP3 inflammasome activity and cytotoxicity have not fully been elucidated. The objective of this body of work was to further define common yet critical mechanisms that cause and/or mediate NLRP3 inflammasome activity following exposure to bioactive particles. In these studies we demonstrate that bioactive particles including silica and engineered nanomaterials cause lysosome membrane permeabilization (LMP) and the release of lysosomal proteases, which precedes and facilitates NLRP3 inflammasome activation. Bioactive particles cause LMP through a mechanism that requires phagolysosome acidification. LMP and the activation of the NLRP3 inflammasome are required for secretion of pro-inflammatory cytokines and the alarmin High Mobility Group Box 1 (HMGB1). Once secreted, HMGB1 can further drive NLRP3 inflammasome activity through sterile priming, similar to the nonsterile mechanism utilized by endotoxin. A second critical pathway for regulation of the NLRP3 inflammasome was autophagy. Mice with macrophages deficient in autophagy had greater inflammation and chronic disease following silica exposure, supporting a protective anti-inflammatory role for autophagic activity. Together, these data reveal novel critical mechanisms in the regulation of NLRP3 inflammasome activity following bioactive particle exposure, and provide multiple potential therapeutic targets for the suppression of inflammation and disease.

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© Copyright 2016 Forrest Connell Jessop