Severity of Repetitive Mild Traumatic Brain Injury Depends on Microglial Heme Oxygenase-1 and Carbon Monoxide

Abstract

Traumatic brain injury is one of the most common cerebral incidences worldwide. Repetitive mild traumatic brain injuries occurring, for example, in athletes or victims of abuse, can cause chronic neurodegeneration due to neuroinflammation, in which the crosstalk between reactive astrocytes and activated microglia is crucial for modulating neuronal damage. The inducible enzyme heme oxygenase-1 and its product carbon monoxide are known to be ascribed neuroprotective and anti-inflammatory properties. We caused repetitive mild traumatic brain injuries in wild-type mice compared to mice without microglial heme oxygenase-1 expression. Additionally, mice were treated daily with either air or carbon monoxide exogenously. In wild-type mice, we observed enhanced microglia activation and astrogliosis as well as vasodilation after repetitive trauma. In heme oxygenase-1 knockout mice, we observed enhanced activation of microglia and astrocytes at baseline pretrauma with a lack of an adequate inflammatory response to repetitive injury. However, the knockout led to enhanced NF-κB and IFNγ expression in the post-trauma period. Carbon monoxide exerted neuroprotection, as suggested by reduced wake-up times in mice and by beneficially altering inflammation post-traumatic brain injury. This study further underlines the crucial role of the heme oxygenase-1/carbon monoxide system in the modulation of neuronal damage and the associated neuroinflammatory response after repetitive traumatic brain injury.