Author ORCID Identifier

https://orcid.org/0000-0001-6982-7725

Date Available

9-17-2021

Year of Publication

2021

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Physiology

First Advisor

Dr. John C. Gensel

Abstract

Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by macrophages consisting of resident microglia and infiltrating monocytes. These chronically activated SCI macrophages adopt a pro-inflammatory, pathological state that continues to cause additional damage after the initial injury and inhibits recovery. While the roles of macrophages in SCI pathophysiology are well documented, the factors contributing to this maladaptive response are poorly understood. Here, we identify the detrimental effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA2) in myelin- mediated potentiation of pro-inflammatory macrophage activation. Macrophage- mediated inflammatory responses are promising therapeutic targets; however, there are very few therapeutic options to treat SCI and none that target macrophages. Here, we provide evidence that treatment with the immunomodulatory antibiotic azithromycin (AZM), initiated after SCI, improves recovery by targeting macrophage activation. There is an urgent need for the development of new therapies for the treatment of SCI. Macrophage-targeted therapies hold great promise; however, these treatment candidates require additional development before they can advance towards clinical use. Here we discuss the continued development of cPLA2 as a therapeutic target, the steps necessary to advance AZM towards clinical use, and lastly, we review additional macrophage-targeted therapies currently in development. Collectively this body of work identifies key mechanisms driving macrophage pathophysiology after SCI and identifies macrophage-targeted therapies that reduce this neuroinflammation to improve recovery after SCI.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.381

Funding Information

National Institutes of Health National Institute of Neurological Disorders and Stroke T32 NS077889: Neurobiology of CNS Injury and Repair. PI: Edward Hall, PhD. (2016-2018)

National Institutes of Health National Institute of Neurological Disorders and Stroke F31 NS105443: Contributions of Myelin Derived Arachidonic Acid to Macrophage Polarization and Secondary Damage after Spinal Cord Injury. PI: Timothy Kopper. (2018-2021)

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