IGF-1 and Innate Immunity in Neonatal Brain Injury

Abstract Neonatal Intraventricular hemorrhage (IVH) originates from the underdeveloped germinal matrix, a site of cell rapid cell division adjacent to the lateral ventricles of the brain. IVH leads to brain injury and life-long neurological disability. Within the same time frame that neonatal IVH occurs, the brain is rapidly producing the cells needed for myelination. Oligodendrocytes, the myelin-forming cells of the brain, are derived from oligodendrocyte progenitor cells (OPCs). OPCs are fragile cells - exquisitely sensitive to many factors present across multiple neurological diseases such as excitotoxicity, inflammatory cytokines, and oxidative stress. Across a wide spectrum of neurological diseases, neuroinflammation disturbs OPC development. IVH both causes inflammation and leads to white matter pathology. Microglia, the endogenous macrophages of the brain, are the main effectors of neonatal neuroinflammation and are implicated in many forms of neonatal brain injury. However, microglia also produce insulin-like growth factor-1 (IGF-1), which is required for normal OPC development. IGF-1 is decreased by other forms of neonatal brain injury but has not been studied in IVH. Our preliminary data indicates that microglia increase production of inflammatory cytokines and reduce IGF-1 production after exposure to hemoglobin. Both of these effects could impair OPC development. Supplementing IGF-1 after IVH may be a powerful therapy because IGF-1 not only supports OPC health, but also modulates inflammation and reduces production of cytokines that are harmful to OPCs. These dual roles of IGF-1: supporting OPC development and altering the phenotype of immune cells (including microglia), makes it an excellent candidate for treating IVH in which both inflammation and white matter pathology occur. This project is designed to better understand how microglia respond to IVH, with a focus on how hemoglobin and IGF-1 affect inflammation and OPC development. It is also designed to trace OPC fate after IVH and determine if myelination failure is due to OPC loss versus maturation failure. We will trial IGF-1 as a therapy for IVH, and test its ability to modulate microglial activation and improve myelination.