Characterizing the role of myeloid-specific heme oxygenase-1 (HO-1) in the regulation of circadian rhythmicity, neuroinflammation and neuronal injury following brain trauma
Final Report Abstract
In this two-part project, we first describe how the HO-1/CO (heme oxygenase 1; carbon monoxide) system interacts with mechanisms controlling circadian rhythm to determine the extent of neuronal injury after hemorrhagic stroke. We employed both in vitro and in vivo studies to demonstrate that the presence of HO-1 specifically in microglia directly influences the expression of circadian control genes and that changes in the circadian gene expression profile are linked to processes critical to injury response after hemorrhage, such as CD36-mediated erythrophagocytosis and the neuroinflammatory response. Additional human observational data link both circadian control genes and HO-1 to functional neurological outcome and delirium, providing evidence for the clinical relevance of these pathways and for their potential use as prognostic markers in traumatic and hemorrhagic brain injury. We continue to provide evidence for a delicate circadian crosstalk via direct neural interaction between peripheral organs such as the kidney and the central nervous system that might influence susceptibility to injury of both the brain after hemorrhage and peripheral organs. In the second part of this project, we start with a characterization of the reactive transformation of astrocytic glial cells in response to traumatic brain injury and demomstrate that the presence of HO-1 specifically in microglia critically influences the transformation towards harmful vs. protective astrocytic polarization. Furthermore, in vitro, in vivo and correlative human data demontrate a differential role of microglial and astrocytic HO-1 in determining neuroinflammation and neuronal injury after head trauma, with HO-1-specific changes in glial cell activation, cytokine production, Tolllike receptor (TLR) expression and ultimately neuronal damage after traumatic injury. Collectively, these results provide further insight into the pathophysiology of neuronal damage after hemorrhagic and traumatic brain injury and how interference with HO-1 and circadian control might be associated with improved neurological outcome. They demand further basic science and clinical investigations studying the potential neuroprotective properties of interaction with these physiological systems.
Publications
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Neuroprotection after Hemorrhagic Stroke Depends on Cerebral Heme Oxygenase-1. Antioxidants, 8(10), 496.
Kaiser, Sandra; Frase, Sibylle; Selzner, Lisa; Lieberum, Judith-Lisa; Wollborn, Jakob; Niesen, Wolf-Dirk; Foit, Niels Alexander; Heiland, Dieter Henrik & Schallner, Nils
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Carbon monoxide controls microglial erythrophagocytosis by regulating CD36 surface expression to reduce the severity of hemorrhagic injury. Glia, 68(11), 2427-2445.
Kaiser, Sandra; Selzner, Lisa; Weber, Janick & Schallner, Nils
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Expression of HO1 and PER2 can predict the incidence of delirium in trauma patients with concomitant brain injury. Scientific Reports, 11(1).
Steimer, Matti; Kaiser, Sandra; Ulbrich, Felix; Kalbhenn, Johannes; Bürkle, Hartmut & Schallner, Nils
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Patients with Subarachnoid Hemorrhage Exhibit Disturbed Expression Patterns of the Circadian Rhythm Gene Period-2. Life, 11(2), 124.
Frase, Sibylle; Kaiser, Sandra; Steimer, Matti; Selzner, Lisa; Foit, Niels Alexander; Niesen, Wolf-Dirk & Schallner, Nils
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Temporal Expression Pattern of Hemoxygenase-1 Expression and Its Association with Vasospasm and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage. Neurocritical Care, 36(1), 279-291.
Frase, Sibylle; Steimer, Matti; Selzner, Lisa; Kaiser, Sandra; Foit, Niels Alexander; Niesen, Wolf-Dirk & Schallner, Nils
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Circadian dependency of microglial heme oxygenase-1 expression and inflammation determine neuronal injury in hemorrhagic stroke. Journal of Inflammation, 20(1).
Henrich, Luise; Kiessling, Iva; Steimer, Matti; Frase, Sibylle; Kaiser, Sandra & Schallner, Nils
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Neuroprotection via Carbon Monoxide Depends on the Circadian Regulation of CD36-Mediated Microglial Erythrophagocytosis in Hemorrhagic Stroke. International Journal of Molecular Sciences, 25(3), 1680.
Kaiser, Sandra; Henrich, Luise; Kiessling, Iva; Loy, Benedikt & Schallner, Nils
