Neuroprotection by Driving Microglia M2 Polarization after Traumatic Brain Injury: Therapeutic and Mechanistic Approaches

Project: Research

View graph of relations

Description

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide results in neurological deficits. TBI is a progressive disorder that worsens over time due largely to secondary injury occurs days after irreversible mechanical primary injury. Therapeutic intervention therefore focuses on limiting secondary damage caused by inflammatory response that persists for months to years after TBI. Microglia are innate immune cells of the central nervous system (CNS) that possess a double-edge sword function, and play key roles in secondary damage. Following TBI, activated microglia acquire heterogeneous phenotypes namely M1 or M2 microglia secreting cytokines/chemokines either exacerbate (M1) or limit (M2) tissue damage. M1 microglia secrete pro-inflammatory cytokines (neurotoxic). M2 microglia not only produce anti-inflammatory cytokines and neurotrophic factors that are neuroprotective, but also displace increase capacity in chemotaxis and phagocytosis. Unlike the persistent M1 activation of microglia, activation of M2 microglia is transient that phases out within days after TBI. Therefore, there is an urge to develop therapy direct at shifting pro-inflammatory M1 to anti-inflammatory M2 microglia, to improve neurological function recovery after TBI.Low-dose ionizing radiation (LDIR) such as X-ray enhances adaptive response such as average life expectancy extension, stimulation of immune system, wound healing, cell growth stimulation and neuroprotection in animal models of neurodegenerative diseases, primarily due to immunomodulation. LD X-ray increases anti-inflammatory cytokine production and chemotaxis in human macrophages. LD X-ray (radiotherapy) has been used for decades in treating patients with arthritis.To test the hypothesis that LD X-ray promotes M1 to M2 phenotypic switch after TBI, our results showed that LD X-ray induced upregulation of mRNA expression of M2 markers, a panel of neurotrophic factors, and genes involved in phagocytosis, while keeping the expression of M1 markers unchanged in cultured mouse microglia. In vivo promoting effect of LD X-ray was confirmed by showing increased microglial cell density near the injury site, increased neuronal survival, reduced glial scar, and faster wound healing after TBI in adult and postnatal mice.Current proposal aims to study in vivo functional recovery of TBI mice after LD X-ray irradiation. We first plan to identify the optimal irradiation strategy (partial irradiation of head) to induce maximal motor and cognitive recovery tested by neurobehavioral tests. We will also identify key cytokines/chemokines responsible for the beneficial effect of LD X-ray irradiation by in vivo microdialysis. Our ultimate goal is to establish a microglia-based therapy for TBI and other CNS disorders.

Detail(s)

Project number9042614
Grant typeGRF
StatusActive
Effective start/end date1/01/19 → …