A BRAVE NEURO WORLD: UNCOVERING THE ROLE OF RON RECEPTOR TYROSINE KINASE IN NEUROINFLAMMATION
Open Access
- Author:
- Dey, Adwitia
- Graduate Program:
- Integrative and Biomedical Physiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 18, 2018
- Committee Members:
- Dr.Pamela Hankey Giblin, Dissertation Advisor/Co-Advisor
Dr.Pamela Hankey Giblin, Committee Chair/Co-Chair
Dr.Robert Paulson, Committee Member
Dr.Na Xiong, Committee Member
Dr.A Catharine Ross, Outside Member
Dr.Margherita Cantorna, Committee Member - Keywords:
- inflammation
neurobiology
microglia
neurophysiology
aging-brain
neurodegeneration
multiple sclerosis
diet-induced obesity - Abstract:
- Neurodegenerative diseases are well characterized by severe neuroinflammation, however very little is known about how chronic inflammation develops in the CNS, challenges neuroimmune function and in turn regulates neural disease progression. The source of inflammation underlying neurodegeneration has been linked to a decrease in CNS M2-macrophage activation. Receptor D’Origine Nantais (Ron) is a transmembrane tyrosine-kinase receptor is expressed on tissue resident M2-macrophages and now, confirmed on CNS microglia. The objective this dissertation was to investigate whether global Ron expression plays a role in CNS health and disease. We aimed to evaluate tissue and cellular neuroinflammation associated with macrophage heterogeneity in context of Ron expression in mice. From this dissertation we aim to elucidate whether the global expression of Ron plays a protective role in neuroinflammation. To establish whether Ron expression is essential to CNS health we implemented transgenic global Ron knockout mice in all our models. For AIM-1, we hypothesized that a loss of the Ron receptor will result in increased M1 macrophage-associated neuroinflammation in models of aggressive and chronic diseases. These primary studies have elucidated constitutive Ron expression in the CNS is necessary for healthy development and metabolic homeostasis. A loss of Ron responsiveness to its ligand, macrophage stimulating protein (MSP), exacerbated disease-mediated neuroinflammation in an aggressive murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) and high-fat diet intervention induced chronic inflammation. In both disease models, a loss of Ron supported increased M1-macrophage mediated neuroinflammation. These experiments performed in the earlier aim have identified a protective role for the Ron receptor in CNS health. However, the underlying mechanism by which Ron signaling regulates neuroprotection remains to be characterized. Recent advents in neurodegenerative disease have focused on the role of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and interleukin (IL)-1β accumulation in microglia. Ron expression on tissue resident macrophages have been demonstrated to attenuate inflammation in models of peripheral inflammation. Herein AIM-2 objectives were to elucidate a potential novel signaling pathways underlying Ron mediated neuroprotection. We hypothesized that the Ron receptor plays a role in attenuating inflammation underlying neurodegeneration, at least in part, by limiting inflammasome activation. For this aim, we implemented a more aggressive model diet-induced atherosclerosis associated inflammation. We illustrated MSP-dependent activation of Ron whether in vivo or with human CHME-3 cells in vitro, attenuated CNS NLRP3-inflammasome activation, cytokine maturation and secretion of IL-1β and IL-18. A loss of Ron exacerbated hippocampal inflammasome expression, a region of the CNS most vulnerable to aging associated inflammation. This is the first study to illustrate the homeostatic role of Ron in CNS health and inflammasome associated-activation underlying Ron mediated protection in neuroinflammation. In doing so the results have supported on-going studies into the protective role of Ron in amyloidosis and tauopathy. Altogether this dissertation was able to establish a significant role of Ron expression and its correlation to neuroinflammation. This increased grade inflammation was interrelated to M1-mediated injury and inflammasome expression in the absence of global Ron expression. The results from this study highlight the potential of macrophage heterogeneity in regulating the degree of inflammation underlying neuropathology.