Modulating the Immune Response Towards a Neuroregenerative Peri-injury Milieu After Cerebral Hemorrhage

Abstract

Cerebral hemorrhages account for 15-20 % of stroke sub-types and have very poor prognoses. The mortality rate for cerebral hemorrhage patients is between 40 and 50 %, of which at least half of the deaths occur within the first 2 days, and 75 % of survivors are incapable of living independently after 1 year. Current emergency interventions involve lowering blood pressure and reducing intracranial pressure by controlled ventilations or, in the worst case scenarios, surgical intervention. Some hemostatic and coagulatherapeutic interventions are being investigated, although a few that were promising in experimental studies have failed in clinical trials. No significant immunomodulatory intervention, however, exists for clinical management of cerebral hemorrhage. The inflammatory response following cerebral hemorrhage is particularly harmful in the acute stage because blood-brain barrier disruption is amplified and surrounding tissue is destroyed by secreted proteases and reactive oxygen species from infiltrated leukocytes. In this review, we discuss both the destructive and regenerative roles the immune response play following cerebral hemorrhage and focus on microglia, macrophages, and T-lymphocytes as the primary agents directing the response. Microglia, macrophages, and T-lymphocytes each have sub-types that significantly influence the over-arching immune response towards either a pro-inflammatory, destructive, or an anti-inflammatory, regenerative, state. Both pre-clinical and clinical studies of cerebral hemorrhages that selectively target these immune cells are reviewed and we suggest immunomodulatory therapies that reduce inflammation, while augmenting neural repair, will improve overall cerebral hemorrhage outcomes.

Keywords: Germinal matrix hemorrhage; Inflammation; Intracerebral hemorrhage; Intraventricular hemorrhage; Lymphocytes; Macrophages; Microglia.