ORCID

http://orcid.org/0000-0003-3519-9382

Date of Award

Summer 8-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Macrophages are innate immune cells that protect against pathogens and maintain tissue integrity. In vertebrates, macrophages reside in every tissue where they perform specific functions from early development through adulthood. While macrophages provide important functions across all tissues, a major focus in recent years has been the role of resident brain macrophages, known as microglia, in neurodegeneration. As microglia have been shown to affect brain development, homeostasis, and disease, they demonstrate how immune cells critically mediate neurological health and point to the broader significance of neuroimmune interactions, or the coordinated actions of the nervous and immune systems for maintaining tissue health. However, the nervous system also includes peripheral nerves, which not only enable the brain to communicate with the external environment, but are indispensable for maintaining bodily functions. While the peripheral nervous system (PNS) also contains resident macrophages, they are much less characterized than brain microglia. For my dissertation, I set out to investigate PNS macrophages and compare them with their counterparts in the central nervous system (CNS). My work began with the identification and transcriptional characterization of PNS macrophage across peripheral nerves. I found that self-maintaining PNS macrophages were transcriptionally related to CNS microglia and expressed many transcripts previously thought to be exclusive to microglia. PNS macrophages also expressed unique transcripts reflecting tissue-specific roles and, remarkably, genes previously identified to be upregulated by activated microglia during aging, neurodegeneration, or loss of Sall1. I next examined the developmental features of PNS macrophages and found that they rely on IL-34 for maintenance and arise from both embryonic and hematopoietic precursors. The majority of transcriptional signatures in PNS macrophages did not differ by ontogeny, suggesting that nerve environment specifies PNS macrophage identity at steady state. Finally, my work reveals the responsiveness of PNS macrophages to changes in nerve environment. PNS macrophages shifted their gene expression to become more microglia-like in a dysmyelination model. After injury, PNS macrophages strikingly expressed a set lipid-handling genes that resembled “foamy” macrophages. Targeting of lipid metabolism by high fat diet improved nerve regeneration in a manner suggesting partial dependence on PNS macrophages. Collectively, these findings uncover shared and unique features between neural resident macrophages, emphasize the role of nerve environment for shaping PNS macrophage identity, and point to the therapeutic potential for PNS macrophages in nervous system disorders.

Language

English (en)

Chair and Committee

Gwendalyn J. Randolph Jeffrey Milbrandt

Committee Members

Marco Colonna, Haina Shin, Brian Kim, Hongzhen Hu,

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