Regulation by the Ron Receptor Tyrosine Kinase to Attenuate Central Nervous System Inflammation in a Model of Atherosclerosis

Open Access
Author:
Alnemri, Diana Mary
Area of Honors:
Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Pamela Hankey-Giblin, Thesis Supervisor
  • James Harold Marden, Honors Advisor
Keywords:
  • Central Nervous System
  • Inflammation
  • Ron
  • Microglia
  • Neuron
Abstract:
Neurodegeneration is the leading cause of cognitive impairment leading to functional disability in aging populations. The debilitating symptoms and progression of neurodegenerative diseases, such as Alzheimer's Disease, aging associated dementia, and Parkinson's disease, are mainly characterized by chronic central nervous system inflammation. The Ron receptor tyrosine kinase (Ron) is expressed in tissue resident cells in the brain, including microglia and neurons. Most importantly, expression of Ron on macrophages has been identified to attenuate inflammation. The objective of this study was to further understand the neuroprotective role of the Ron receptor and its ligand, macrophage-stimulation protein (MSP), in regulating inflammation in the brain in both vascular structures and cells including microglia and astrocytes. Specifically, the significance of the inducible enzyme iNOS in triggering inflammation, as well as the dynamics of NLRP3 inflammasome activation were assessed in the CNS. Apolipoprotein E-knockout (ApoE-/-) and Ron receptor/ApoE-/- double knockout (DKO) transgenic mice were developed and maintained on a high-fat-high-cholesterol diet (HFHCD) for 18 weeks. Immunohistochemical analysis indicated that a loss of Ron lead to the accumulation of smooth-muscle arterial iNOS in small to large CNS vessels (p<0.05), as well as surrounding cellular accumulations of iNOS. Additionally, increases in GFAP concentrations signified microgliosis that was triggered by the loss of Ron. Finally, Ron was observed to attenuate lipopolysaccharide (LPS)-induced activation of the NLRP3 inflammasome upon activation by its ligand, MSP. This study was beneficial in determining the key players involved in neuroprotection by Ron and highlighting the importance of activation by its ligand. By understanding and targeting inflammatory regulators such as the Ron receptor, prevention treatments for chronic inflammation caused by neurodegenerative diseases can be advanced.