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Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice.
Stroke. 2015 Oct; 46(10):2916-25.S

Abstract

BACKGROUND AND PURPOSE

Inflammation-related comorbidities contribute to stroke-induced immune responses and brain damage. We previously showed that hyperlipidemia exacerbates ischemic brain injury, which is associated with elevated peripheral and cerebral granulocyte numbers. Herein, we evaluate the contribution of neutrophils to the exacerbation of ischemic brain injury.

METHODS

Wild-type mice fed with a normal chow and ApoE knockout mice fed with a high cholesterol diet were exposed to middle cerebral artery occlusion. CXCR2 was blocked using the selective antagonist SB225002 (2 mg/kg) or neutralizing CXCR2 antiserum. Neutrophils were depleted using an anti-Ly6G antibody. At 72 hours post ischemia, immunohistochemistry, flow cytometry, and real-time polymerase chain reaction were performed to determine cerebral tissue injury and immunologic changes in the blood, bone marrow, and brain. Functional outcome was assessed by accelerated rota rod and tight rope tests at 4, 7, and 14 days post ischemia.

RESULTS

CXCR2 antagonization reduced neurological deficits and infarct volumes that were exacerbated in hyperlipidemic ApoE-/- mice. This effect was mimicked by neutrophil depletion. Cerebral neutrophil infiltration and peripheral neutrophilia, which were increased on ischemia in hyperlipidemia, were attenuated by CXCR2 antagonization. This downscaling of neutrophil responses was associated with increased neutrophil apoptosis and reduced levels of CXCR2, inducible nitric oxide synthase, and NADPH oxidase 2 expression on bone marrow neutrophils.

CONCLUSIONS

Our data demonstrate a role of neutrophils in the exacerbation of ischemic brain injury induced by hyperlipidemia. Accordingly, CXCR2 blockade, which prevents neutrophil recruitment into the brain, might be an effective option for stroke treatment in patients with hyperlipidemia.

Authors+Show Affiliations

From the Department of Neurology (J.H., P.S., D.M.H., T.R.D.), Department of Pediatrics I (J.H.), and Institute of Experimental Immunology and Imaging, University Duisburg-Essen (M.G.), University Hospital Essen, Essen, Germany; and Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City (T.E.L.). josephine.herz@uk-essen.de thorsten.doeppner@uk-essen.de.From the Department of Neurology (J.H., P.S., D.M.H., T.R.D.), Department of Pediatrics I (J.H.), and Institute of Experimental Immunology and Imaging, University Duisburg-Essen (M.G.), University Hospital Essen, Essen, Germany; and Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City (T.E.L.).From the Department of Neurology (J.H., P.S., D.M.H., T.R.D.), Department of Pediatrics I (J.H.), and Institute of Experimental Immunology and Imaging, University Duisburg-Essen (M.G.), University Hospital Essen, Essen, Germany; and Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City (T.E.L.).From the Department of Neurology (J.H., P.S., D.M.H., T.R.D.), Department of Pediatrics I (J.H.), and Institute of Experimental Immunology and Imaging, University Duisburg-Essen (M.G.), University Hospital Essen, Essen, Germany; and Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City (T.E.L.).From the Department of Neurology (J.H., P.S., D.M.H., T.R.D.), Department of Pediatrics I (J.H.), and Institute of Experimental Immunology and Imaging, University Duisburg-Essen (M.G.), University Hospital Essen, Essen, Germany; and Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City (T.E.L.).From the Department of Neurology (J.H., P.S., D.M.H., T.R.D.), Department of Pediatrics I (J.H.), and Institute of Experimental Immunology and Imaging, University Duisburg-Essen (M.G.), University Hospital Essen, Essen, Germany; and Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City (T.E.L.).

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26337969

Citation

Herz, Josephine, et al. "Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice." Stroke, vol. 46, no. 10, 2015, pp. 2916-25.
Herz J, Sabellek P, Lane TE, et al. Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice. Stroke. 2015;46(10):2916-25.
Herz, J., Sabellek, P., Lane, T. E., Gunzer, M., Hermann, D. M., & Doeppner, T. R. (2015). Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice. Stroke, 46(10), 2916-25. https://doi.org/10.1161/STROKEAHA.115.010620
Herz J, et al. Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice. Stroke. 2015;46(10):2916-25. PubMed PMID: 26337969.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice. AU - Herz,Josephine, AU - Sabellek,Pascal, AU - Lane,Thomas E, AU - Gunzer,Matthias, AU - Hermann,Dirk M, AU - Doeppner,Thorsten R, Y1 - 2015/09/03/ PY - 2015/06/28/received PY - 2015/07/16/accepted PY - 2015/9/5/entrez PY - 2015/9/5/pubmed PY - 2015/12/29/medline KW - CXCR2 KW - brain injury KW - hyperlipidemia KW - inflammation KW - neutrophils KW - stroke SP - 2916 EP - 25 JF - Stroke JO - Stroke VL - 46 IS - 10 N2 - BACKGROUND AND PURPOSE: Inflammation-related comorbidities contribute to stroke-induced immune responses and brain damage. We previously showed that hyperlipidemia exacerbates ischemic brain injury, which is associated with elevated peripheral and cerebral granulocyte numbers. Herein, we evaluate the contribution of neutrophils to the exacerbation of ischemic brain injury. METHODS: Wild-type mice fed with a normal chow and ApoE knockout mice fed with a high cholesterol diet were exposed to middle cerebral artery occlusion. CXCR2 was blocked using the selective antagonist SB225002 (2 mg/kg) or neutralizing CXCR2 antiserum. Neutrophils were depleted using an anti-Ly6G antibody. At 72 hours post ischemia, immunohistochemistry, flow cytometry, and real-time polymerase chain reaction were performed to determine cerebral tissue injury and immunologic changes in the blood, bone marrow, and brain. Functional outcome was assessed by accelerated rota rod and tight rope tests at 4, 7, and 14 days post ischemia. RESULTS: CXCR2 antagonization reduced neurological deficits and infarct volumes that were exacerbated in hyperlipidemic ApoE-/- mice. This effect was mimicked by neutrophil depletion. Cerebral neutrophil infiltration and peripheral neutrophilia, which were increased on ischemia in hyperlipidemia, were attenuated by CXCR2 antagonization. This downscaling of neutrophil responses was associated with increased neutrophil apoptosis and reduced levels of CXCR2, inducible nitric oxide synthase, and NADPH oxidase 2 expression on bone marrow neutrophils. CONCLUSIONS: Our data demonstrate a role of neutrophils in the exacerbation of ischemic brain injury induced by hyperlipidemia. Accordingly, CXCR2 blockade, which prevents neutrophil recruitment into the brain, might be an effective option for stroke treatment in patients with hyperlipidemia. SN - 1524-4628 UR - https://www.unboundmedicine.com/medline/citation/26337969/Role_of_Neutrophils_in_Exacerbation_of_Brain_Injury_After_Focal_Cerebral_Ischemia_in_Hyperlipidemic_Mice_ L2 - http://www.ahajournals.org/doi/full/10.1161/STROKEAHA.115.010620?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -