Implications of microglial and macrophage nadph oxidase 2 (nox2) enzyme activation in neuroinflammation

Authors
Muthukumarasamy, Iswarya
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Other Contributors
Hurley, Jennifer, M.
Koffas, Mattheos
Karande, Pankaj
Zha, Helen
Dordick, Jonathan, S.
Issue Date
2023-12
Keywords
Chemical engineering
Degree
PhD
Terms of Use
This electronic version is a licensed copy owned by Rensselaer Polytechnic Institute (RPI), Troy, NY. Copyright of original work retained by author.
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Abstract
Sustained neuroinflammation has been shown to be a major driving force in the progression of various neurodegenerative diseases. Microglia and infiltrating macrophages in the central nervous system play an important role in the progression of neuroinflammation through the release of a variety of inflammatory factors. Reactive oxygen species (ROS) released by these immune cells are one such type of inflammatory factor that result in oxidative stress, a hallmark of neuroinflammation. Thie release of ROS is facilitated by the enzyme NADPH Oxidase Isoform 2 (NOX2) present in both microglia and macrophages. Along with neuroinflammation, circadian disruption is another characteristic feature of neurodegenerative diseases. While the effect of neuroinflammation and circadian disruption on the progression of neurodegenerative diseases have been studied individually, knowledge of the interaction between the two is still lacking.In this thesis, the implications of NOX2 activation were explored with relevance to neuroinflammation by investigating its interaction with the microglial and macrophage circadian clock and other inflammatory mediators. First, the effect of NOX2 activation and inhibition on the microglial circadian clock was established. For this, the BV2 mouse microglial cell line was used as a representative cellular model. We were able to show that inhibition of NOX2 resulted in the retention of the circadian clock function in BV2 microglia even under pro-inflammatory activation. Second, the observations made in BV2 microglia were confirmed in primary mouse bone marrow-derived macrophages. We found that similar to BV2 microglia, NOX2 inhibition resulted in an active circadian clock in macrophages under pro-inflammatory activation. Third, having established the interaction between NOX2 activation and the circadian clock, we investigated how the pathological nature of the macrophages affected their response toward NOX2 activation and inhibition. For this, macrophages from mice subjected to circadian disruption and neurodegenerative disease-mediated neuroinflammation were subjected to NOX2 inhibition. We found that NOX2 inhibition was able to reduce ROS levels irrespective of the macrophage type. Finally, we investigated the interaction of NOX2 with another important inflammatory mediator in microglia, cyclophilin A. For this, the mouse BV2 and human HMC3 microglial cell lines were used as cellular models. We obtained preliminary information indicating the potential interaction between NOX2 and cyclophilin A in microglial cells. In combination, these studies provide mechanistic insights into the different ways in which NOX2 could be targeted to reduce microglia and macrophage-mediated inflammation with relevance to neuroinflammation.
Description
December2023
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Publisher
Rensselaer Polytechnic Institute, Troy, NY
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Rensselaer Theses and Dissertations Online Collection
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