Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1
Nils Schallner, … , Leo E. Otterbein, Khalid A. Hanafy
Nils Schallner, … , Leo E. Otterbein, Khalid A. Hanafy
Published July 1, 2015; First published May 26, 2015
Citation Information: J Clin Invest. 2015;125(7):2609-2625. https://doi.org/10.1172/JCI78443.
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Research Article Neuroscience

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

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.

Authors

Nils Schallner, Rambhau Pandit, Robert LeBlanc III, Ajith J. Thomas, Christopher S. Ogilvy, Brian S. Zuckerbraun, David Gallo, Leo E. Otterbein, Khalid A. Hanafy

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Figure 1

Aggravated neuronal injury after SAH due to HO inhibition with SnPP IX.

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Aggravated neuronal injury after SAH due to HO inhibition with SnPP IX. ...
(A) Representative (n = 6) H&E-stained cross sections of the MCA 7 days after SAH in animals treated with saline or the HO inhibitor SnPP (original magnification, ×40). (B) Quantification of MCA vasospasm, defined as the quotient of LR and WL. P = 0.147 for SAH plus saline versus SAH plus SnPP (2-tailed Student’s t test; n = 6). (C) Representative images (original magnification, ×20; n = 6) from TUNEL staining (red) of the DG and cortex of mice that received SAH plus saline or SnPP treatment 7 days after injury. Nuclei were counterstained with Hoechst 33258 (blue). (D) Quantification of TUNEL-positive cells per microscopic field in the designated brain regions. *P = 0.0413 (DG) and **P = 0.015 (cortex) for SAH plus saline versus SAH plus SnPP (2-tailed Student’s t test; n = 6). (E) Number of total errors in spatial memory function by Barnes maze assessment. Graph shows test results on the days after spatial reversal. *P = 0.0071 (day 0), **P < 0.0001 (day 1), ***P < 0.0001 (day 2), and #P = 0.0007 (day 3) for SAH plus saline versus SAH plus SnPP (2-way ANOVA; n = 9). (F) Total latency in seconds for spatial memory function testing by Barnes maze test. *P < 0.0001 (days 0–3) for SAH plus saline versus SAH plus SnPP (2-way ANOVA; n = 9).