Characterizing the role of myeloid-specific heme oxygenase-1 (HO-1) in the regulation of circadian rhythmicity, neuroinflammation and neuronal injury following brain trauma

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Traumatic brain injury (TBI) is the leading cause of death and disability related to trauma worldwide. The high social and economic impact calls for a better understanding of this devastating disease. The heme oxygenase (HO) enzyme degrades heme to biliverdin, iron and carbon monoxide (CO). Induction of HO-1 isoform constitutes protection in different organ systems including the central nervous system. We have previously identified a novel role for HO-1 in microglia in response to hemorrhage in that microglial HO-1 expression mediates clearance of blood but also produces the gaseous molecule CO that in turn can regulate various cellular pathways. The exact molecular mechanisms of how HO-1 influences neuronal injury remain to be elucidated. Own preliminary data suggest that HO-1 regulates the activation and polarization of both microglia and other glia cells in a CO-dependent manner. These results suggest that reactive transformation of glial cells due to inflammatory stimuli such as HO-1-controlled CO production may modulate neuronal damage and functional impairment in patients via neuronal pathways yet to be determined. One such neuronal pathway could be the molecular feedback loop controlling circadian rhythmicity: There is a striking correlation between neuronal injury following stroke or trauma and the organism’s internal circadian rhythm. Circadian rhythmicity not only determines sleep-wake cycles but nearly every physiological function. On a molecular basis, it is generated by a family of “clock genes”, consisting of several transcription factors and regulatory proteins such as Period 2. Disturbance or deficiency in their activity leads to cardiovascular and central nervous system disease, while increased activity especially of Period 2 has been shown to be protective. Own human data suggest a role especially for Period 2 in influencing the incidence of delirium, neuronal outcome and acute kidney injury following hemorrhagic or traumatic brain injury. An interesting link has been shown to exist between the circadian auto-regulatory feedback loop and the HO-1-CO enzyme system: transcriptional activity of "clock genes" has been shown to be CO-dependent. The HO-1/CO system can indeed influence circadian rhythmicity and neuronal outcome after hemorrhagic stroke and is itself regulated in a circadian manner. Currently, we are further exploring this important and novel function in a project deciphering the crosstalk between central and peripheral circadian rhythmicity following organ injury. In this novel proposed project, we would like to extent our knowledge of the mechanisms related to injury after brain trauma and how the HO-1/CO enzyme system, via regulation of circadian rhythmicity, serves as a central protective regulator in this devastating disease.