Author ORCID Identifier

0000-0002-1456-2181

Date of Graduation

5-2022

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Jaroslaw Aronowski, PhD

Committee Member

Louise D. McCullough, MD, PhD

Committee Member

Scott E. Evans, MD

Committee Member

Amber U. Luong, MD, PhD

Committee Member

J Willam Lindsey, MD

Committee Member

Pamela L. Wenzel, PhD

Abstract

Aging affects immunologic responses by a global immune system suppression, including dysregulation of cytokine mediators, leading to increased inflammation throughout all systems, termed inflammaging. However, understanding healthy aging mechanisms can bypass this effect. Inflammaging also leads to poor outcomes during brain injury, making immune-targeting therapeutics tantamount to overall brain health and longevity. Moreover, sex affects disease etiology and severity through hormonal and chromosomal sex, as the X chromosome contains most immunology-based genes. Androgens have a generally suppressive effect on the immune system. Additionally, when immune responses are mounted, males are better at CD4+ T cell type (Th1) responses, while females prefer Th2 responses. As tissue-resident innate lymphoid cells (ILC) are novel immune cells that are the innate complement to T cells, understanding their role in aging and sex differences is imperative.

Here, ILCs are characterized within various C57Bl6/J mice tissues and defined cytokine output of group 2 innate lymphoid cells (ILC2s) within aging and sex difference models using flow cytometry. Moreover, aging increases susceptibility to many diseases, including those in the brain. Therefore, this study elucidates ILC2/microglia immune crosstalk from brain tissue in vitro. Experiments included conditioned media transfers from stimulated ILC2s from young and aged brains to quiescent microglia and assessed their morphologic, genomic, proteomic, and functional changes using microscopy, qRT-PCR, Western immunoblotting, and phagocytosis assays. Here, microglia morphology became more complex, indicating microglial priming. Moreover, microglia increased reparative mRNA transcripts and phagocytic function, augmented by aged ILC2s. ILC2 soluble factors polarize microglia to a reparative phenotype and maintain this in aging.

Keywords

innate lymphoid cells, neuroinflammation, ILC1, ILC2, ILC3, aging, sex differences, microglia, polarization

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