Macrophage Senescence and Immune Dysfunction in Cystic Fibrosis: Characterization of Senescence-Associated Profiles and Responses to Environmental Stressors Restricted; Files Only

Abstract

      Cystic fibrosis (CF) is an autosomal recessive disease¹ caused by mutations in the cystic fibrosis transmembrane conductance regulator gene and is clinically characterized with a state of chronic airway infection and chronic inflammation. Despite improved survival with modern therapies, people with CF (pwCF) continue to experience progressive immune dysfunction². This persistent dysfunction is in part characterized by reduced macrophage functionality, such as impaired phagocytosis, chronic inflammatory signaling, and reduced intracellular killing^2,3. From this phenotype and prior research showing elevations in relevant blood markers, we hypothesize that senescence is a potential contributor to macrophage dysfunction in CF. This study aimed to characterize baseline senescence-associated profiles in CF macrophages, their response to environmental stressors, and their potential for recovery through senolytic drugs. To profile senescence in CF macrophages, monocyte-derived macrophages were evaluated for β-galactosidase activity, transcriptional profiles through RT-qPCR, and multiplex cytokine analysis. Macrophage response to environmental stressors was tested through zymosan-based phagocytosis assays. CF macrophages demonstrated increased β-galactosidase activity and no significant changes in transcriptional activity. Cytokine profiling revealed reduced inflammatory cytokine secretion in blood samples and increased regulatory elements for inflammatory cytokines; this is contrary to nasal airway sample where there was no significant difference between CF and non-CF. This suggests that there may be inflammatory suppression mechanisms systemically compared to airways, the primary site of inflammation for pwCF. Following environmental toxin exposure, CF macrophages exhibited increased β-galactosidase activity and a reduction in phagocytic capability. Together these findings support the potential of senescence-associated dysfunction in CF macrophages, demonstrate environmental stressors as uniquely harmful amplifiers of these phenotypes, and highlight senescence as a potential therapeutic target for restoring immune function in pwCF.

Table of Contents

Table of Contents

Introduction - 1

Methodology - 4

Results - 8

Aim 1: Quantification and Comparison of Baseline Senescence Markers in CF versus non-CF macrophages. - 8

Flow cytometry data of baseline β-galactosidase activity suggests elevated functional senescence activity in CF MDMs. - 8

Senescence gene profiles are not altered in baseline CF MDMs. - 8

Secreted cytokine profiles are altered in CF MDMs. - 10

Aim 2: Evaluate the ability of senolytics to eliminate or reverse senescent CF macrophages and restore key antimicrobial and inflammatory responses. - 13

CF macrophages exhibit increased senescence signaling in response to environmental toxin exposure. - 14

Initial Validation of Senolytic Function. - 16

Discussion - 18

Conclusion - 22

References Cited - 23

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Cell Health Sciences, Immunology
Keyword	Senescence Cystic Fibrosis Macrophage
Committee Chair / Thesis Advisor	Levin, Bruce, Emory University
Committee Members	Kopp, Benjamin, Ohio State University Tirouvanziam, Rabindra, Emory University

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