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Defective Immunometabolism Pathways in Cystic Fibrosis Macrophages

Hamilton, Kaitlin
http://orcid.org/0000-0003-0111-8185
http://rave.ohiolink.edu/etdc/view?acc_num=osu161899361218313

Abstract Details

2021, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Background: Mitochondria play a key role in immune defense pathways, particularly for macrophages. We and others have previously demonstrated that cystic fibrosis (CF) macrophages exhibit weak autophagy activity and exacerbated inflammatory responses. Previous studies have revealed that mitochondria are defective in CF epithelial cells, but to date, the connection between defective mitochondrial function and CF macrophage immune dysregulation has not been fully elucidated. Here, we present a characterization of mitochondrial dysfunction in CF macrophages. Methods: Mitochondrial function in wild-type (WT) and CF F508del/F508del murine macrophages was measured using the Seahorse Extracellular Flux analyzer. Mitochondrial morphology was investigated using transmission electron microscopy and confocal microscopy. Mitochondrial membrane potential (MMP) as well as mitochondrial reactive oxygen species (mROS) were measured using TMRM and MitoSOX Red fluorescent dyes, respectively. All assays were performed at baseline and following infection with Burkholderia cenocepacia (B. cenocepacia), a multi-drug resistant bacterium that causes detrimental infections in CF patients. Results: We have identified impaired oxygen consumption in CF macrophages without and with B. cenocepacia infection. We also observed increased mitochondrial fragmentation in CF macrophages following infection. Lastly, we observed increased MMP and impaired mROS production in CF macrophages following infection with B. cenocepacia. Conclusions: The mitochondrial defects identified are key components of the macrophage response to infection. Their presence suggests that mitochondrial dysfunction contributes to impaired bacterial killing in CF macrophages. Our current study will enhance our understanding of the pathobiology of CF and lead to the identification of novel mitochondrial therapeutic targets for CF.
Amal Amer, MD, PhD (Advisor)
Narasimham Parinandi, PhD (Committee Member)
Mark Wewers, MD (Committee Member)
Anne Strohecker, PhD (Committee Member)
94 p.
Biology; Cellular Biology; Immunology
Bacterial infection; Cystic fibrosis; Immunometabolism; Macrophage; Mitochondria; Reactive oxygen species

Recommended Citations

Citations

  • Hamilton, K. (2021). Defective Immunometabolism Pathways in Cystic Fibrosis Macrophages [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu161899361218313

    APA Style (7th edition)

  • Hamilton, Kaitlin. Defective Immunometabolism Pathways in Cystic Fibrosis Macrophages. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu161899361218313.

    MLA Style (8th edition)

  • Hamilton, Kaitlin. "Defective Immunometabolism Pathways in Cystic Fibrosis Macrophages." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu161899361218313

    Chicago Manual of Style (17th edition)

osu161899361218313
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This open access ETD is published by The Ohio State University and OhioLINK.