The role of the inflammasome in the respiratory innate immune response to viruses and pollutants: insights for asthma pathogenesis Public Deposited

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  • March 20, 2019
  • Bauer, Rebecca N.
    • Affiliation: School of Medicine, Curriculum in Toxicology
  • The respiratory mucosal innate immune system is composed of both structural cells, such as airway epithelial cells, and immune cells, such as macrophages, that together determine the appropriate immune response to inhaled stimuli. These cells use pattern recognition receptors to distinguish between harmless and harmful stimuli by recognizing conserved microbial pathogen-associated molecular patterns (PAMPs) and endogenously derived damage-associated molecular patterns (DAMPs) from damaged tissue. Inappropriate immune responses to normally innocuous stimuli underpin the pathogenesis of a number of immune disorders, including asthma, a chronic inflammatory disease of the airway typified by difficulty breathing in response to a trigger. In this dissertation, we explored the contribution of the inflammasome signaling complex to respiratory mucosal host defense against two sources of asthma exacerbation: influenza A virus infection and inhalation of the oxidant air pollutant ozone (O3). The inflammasome is an innate immune complex composed of a pattern recognition receptor, the protease caspase-1, and an adaptor protein (PYCARD) that when formed induces activation of caspase-1-mediated processing of the pro-inflammatory mediators IL-1B and IL-18 or cell death. Our results show that caspase-1 and the inflammasome contribute to the airway epithelial cell innate immune response to influenza and that this pathway is modified by asthma, suggesting a role for caspase-1 in virus-induced asthma exacerbation. Using a mouse model of allergic airway inflammation, we also show that caspase-1 may be involved in the development of allergic asthma, though its function in asthma development is complex. In the context of O3, we found increased presence of several DAMPs that may activate inflammasome signaling in the airway of healthy volunteers exposed to O3, but no evidence to suggest that inflammasome signaling strongly contributes to the innate immune response to O3. Finally, we identified a mechanism by which O3 alters the interaction between epithelial cells and macrophages leading to the accumulation of DAMPs that may activate innate immune responses in the lung. In summary, our results shed light on the function of the inflammasome in the human respiratory innate immune response to viruses and pollutants, and provide insight on the contribution of inflammasome signaling to asthma pathogenesis.
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  • In Copyright
  • Jaspers, Ilona
  • Doctor of Philosophy
Graduation year
  • 2014

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