Igniting inflammation : microglia are pro-inflammatory first responders after ischemic stroke
Abstract/Contents
- Abstract
- Stroke is a cerebrovascular event resulting in cell death in the brain, neurological deficits, and other complications. Stroke is one of the most common causes of death and disability worldwide, but in spite of its prevalence, treatments remain extremely limited. Neuroinflammation after stroke is an appealing therapeutic target, because of its prolonged time course and because it includes multifaceted responses which may either exacerbate or mitigate neuronal death and facilitate injury resolution and repair. Microglia are the brain's resident macrophage population and are central to the neuro-immune response after stroke by becoming activated in response to cellular damage, initiating inflammation, releasing chemokines and pro-inflammatory signaling molecules, clearing dead cells and debris, and secreting growth factors to promote tissue repair. Furthermore, microglia recruit peripheral immune cells into the injured brain, such as monocyte-derived macro-phages, which also contribute to these aspects of the neuro-immune response. Chapter 1 provides an overview of the events in the neuroinflammatory response to ischemic stroke and highlights current knowledge and controversies about microglial functions in post-stroke neuroinflammation. Much is still unknown about which microglial functions are most important to the overall immune response after stroke, and how those functions change over time. Particularly little is known about the pivotal role that microglia play in initiating neuroinflammation after stroke, and the different signals which regulate the microglial and macrophage response. The sympathetic nervous system is activated after stroke, and previous studies indicate that sympathetic neurotransmitters inhibit inflammatory activities of immune cells primarily by acting on beta2-adrenergic receptors. In Chapter 2, I use pharmacological stimulation of beta2-adrenergic signaling and genetic knockout of the beta2-adrenergic receptor from microglia and macrophages to evaluate the extent to which beta2-adrenergic receptor signaling modulates the activation and inflammatory functions of these cells following ischemic stroke. In Chapter 3, I leverage gene expression profiling of ribosome-associated mRNA from microglia to characterize the microglial transcriptional profile in the early response phase after stroke compared to the later sub-acute phase. This work reveals robust pro-inflammatory signaling of microglia during the initiation of post-stroke neuroinflammation and demonstrates that this response changes over time. This analysis also identified several genes strongly upregulated during the acute and sub-acute micro-glial inflammatory responses, and Chapter 4 describes ongoing work to investigate the functional role of some of these molecules in stroke recovery and neuro-immune signaling. Chapter 5 provides a summary of the findings reported in this dissertation, and de-scribes ongoing work and future studies
Description
Type of resource | text |
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Form | electronic resource; remote; computer; online resource |
Extent | 1 online resource |
Place | California |
Place | [Stanford, California] |
Publisher | [Stanford University] |
Copyright date | 2020; ©2020 |
Publication date | 2020; 2020 |
Issuance | monographic |
Language | English |
Creators/Contributors
Author | Lechtenberg, Kendra Joan |
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Degree supervisor | Buckwalter, Marion |
Degree supervisor | Wyss-Coray, Anton |
Thesis advisor | Buckwalter, Marion |
Thesis advisor | Wyss-Coray, Anton |
Thesis advisor | Andreasson, Katrin |
Thesis advisor | James, Michelle (Michelle Louise) |
Thesis advisor | Shatz, Carla J |
Degree committee member | Andreasson, Katrin |
Degree committee member | James, Michelle (Michelle Louise) |
Degree committee member | Shatz, Carla J |
Associated with | Stanford University, Neurosciences Program. |
Subjects
Genre | Theses |
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Genre | Text |
Bibliographic information
Statement of responsibility | Kendra Joan Lechtenberg |
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Note | Submitted to the Neurosciences Program |
Thesis | Thesis Ph.D. Stanford University 2020 |
Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Kendra Joan Lechtenberg
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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