Year of Award

2026

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Andrij Holian

Commitee Members

Christopher Migliaccio, Elizabeth Putnam, Kevan Roberts, Scott Wetzel, Jonathan Shannahan

Keywords

Inflammation, Lysosome membrane permeability, Lysosomes, Macrophage, NLRP3 inflammasome, Sphingolipids

Abstract

Persistent exposure to environmental particles such as crystalline silica results in chronic lung inflammation and fibrosis (silicosis). Similar pathologies occur in diseases driven by endogenous particulates including cholesterol crystals (atherosclerosis), monosodium urate (gout), and amyloid protein aggregates (Alzheimer’s), suggesting a shared lysosome-centered mechanism may underline particle-induced inflammation from diverse sources. Despite the clinical burden of chronic diseases, effective therapies remain limited due to an incomplete understanding of the upstream cellular and molecular mechanisms that mediate inflammation. Alveolar macrophages are the primary sentinel cells in the lung responsible for internalizing inhaled particles in phagolysosomes. However, many environmental particles resist phagolysosome-degradation and permeabilize the phagolysosome membrane. Phagolysosome membrane permeabilization (LMP) facilitates leakage of lysosomal enzymes, triggering activation of the NLRP3 inflammasome and subsequent release of the potent pro-inflammatory cytokine IL-1β. Inhaled particles can also promote mitochondrial reactive oxygen species (mtROS) production, which may also contribute to inflammasome activation. Importantly, both membrane integrity and inflammasome activation are influenced by sphingolipid metabolism, a lipid pathway enriched in lysosomes with key bioactive lipids including sphingomyelin, ceramide, and sphingosine. Sphingosine can be phosphorylated to sphingosine-1-phosphate, a signaling lipid capable of propagating inflammatory responses beyond the lysosome. This research uses pharmacologic inhibitors to interrogate key enzymatic steps in lysosomal sphingolipid metabolism during particleinduced inflammation. Nickel oxide nanoparticles (NiONPs) were used as a model engineered nanomaterial alongside crystalline silica as a positive control. In parallel, silica-specific mechanisms were further examined independent of NiONP exposure. Inhibition of sphingolipid metabolic enzymes was used to investigate this lipid pathway in particle-induced cell death, LMP, and NLRP3 inflammasome activation. Lysosomes were isolated from treated macrophages for lipidomic profiling to define treatment-induced alterations in lysosome lipid composition. Additionally, the relative contributions of LMP and mtROS to inflammasome activation were evaluated. Collectively, these findings identify lysosomal sphingolipid metabolism as a key regulator of particle-induced lysosomal destabilization and NLRP3 inflammasome-driven inflammation in macrophages. Targeting this lipid pathway effectively attenuated downstream inflammatory signaling, highlighting its potential as a therapeutic strategy for chronic inflammatory diseases.

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Available for download on Wednesday, June 23, 2027

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