Thesis Defence: Biliverdin modulates the phagocytic activity of BV-2 murine microglia by the activation of toll-like receptor (TLR)4

Noah Brooks, supervised by Dr. Andis Klegeris, will defend their thesis titled “Biliverdin modulates the phagocytic activity of BV-2 murine microglia by the activation of toll-like receptor (TLR)4″ in partial fulfillment of the requirements for the degree of Master of Science in Biochemistry and Molecular Biology.

An abstract for Noah Brooks’ thesis is included below.

Defences are open to all members of the campus community as well as the general public. Please email andis.klegeris@ubc.ca to receive the Zoom link for this defence.

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Abstract

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, affects over 10% of individuals above age 65. Increasing evidence suggests that disease progression is driven in part by neuroinflammation, a process mediated by microglia, the resident immune cells of the central nervous system (CNS). Chronically reactive microglia can release neurotoxic molecules in response to pro-inflammatory damage-associated molecular patterns (DAMPs) originating from injured or dead cells. One such DAMP is the oxygen-binding prosthetic group heme, which in its protein-free form hemin is elevated in concentration 2.5-fold in AD brains compared to healthy brains. Extracellular hemin promotes pro-inflammatory cytokine production and attenuates the clearance of amyloid β (Aβ) by microglia. Glial heme oxygenase (HO)-1 degrades extracellular hemin into biliverdin, a molecule far less studied than hemin in both the periphery and the CNS. Physiological concentrations of biliverdin in the periphery range from 0.9-6.5 μM; however, prior work in peripheral immune cells demonstrates that supraphysiological levels (50 μM) have anti-inflammatory effects by activating the phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt) pathway to induce interleukin (IL)-10 production and inhibition of toll-like receptor (TLR)4-mediated pro-inflammatory signaling. However, the role of biliverdin within the CNS remains unclear. To address this knowledge gap, my thesis work investigates the effects of biliverdin on murine and human microglia. My findings indicate that biliverdin is cytotoxic towards BV-2 murine microglia and NSC-34 murine neuronal cells at concentrations previously reported to have no effect on peripheral immune cell survival. Biliverdin at non-toxic concentrations significantly enhances the phagocytic activity of BV-2 cells by acting as an agonist of microglial TLR4. Additionally, biliverdin does not affect the production of cytokines such as IL-10 or IP-10 or neurotoxic molecules such as nitric oxide (NO). These findings contrast with the previously reported antagonistic effects of biliverdin towards TLR4 in the periphery, suggesting that it may play a different role in inflammatory processes in the CNS. Collectively, these results expand the current understanding of the biological activity of biliverdin in the CNS by identifying it as a potentially important immunomodulatory molecule in the context of neurodegenerative disease.