Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1

Schallner, Nils, Pandit, Rambhau, LeBlanc III, Robert, Thomas, Ajith J., Ogilvy, Christopher S., Zuckerbraun, Brian S., Gallo, David, Otterbein, Leo E. and Hanafy, Khalid A. (2015). Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. Journal of Clinical Investigation, 125 (7), pp. 2609-2625.

Abstract

Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.

Publication DOI: https://doi.org/10.1172/JCI78443
Divisions: Aston University (General)
Additional Information: The JCI is an open access journal. All research content is freely available immediately upon publication, and all articles published in the JCI are deposited in PubMed Central (PMC). Users are allowed to read, download, print, search, or link to the full texts of the articles under the "fair use" limitations of US copyright law. Funding: NIH (K08 NS078048); HL-071797; HL-076167; and German Research Foundation (DFG) (SCHA 1838/2-1.
Uncontrolled Keywords: Medicine(all)
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2015-07-01
Authors: Schallner, Nils
Pandit, Rambhau
LeBlanc III, Robert
Thomas, Ajith J.
Ogilvy, Christopher S.
Zuckerbraun, Brian S.
Gallo, David
Otterbein, Leo E.
Hanafy, Khalid A.

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