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PMID: 19005067 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The HMGB1 receptor RAGE mediates ischemic brain damage.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 28 ·No. 46 ·2008-11-12 ·Pages 12023-12031

Muhammad S, Barakat W, Stoyanov S, Murikinati S, Yang H, Tracey KJ, Bendszus M, Rossetti G, Nawroth PP, Bierhaus A, Schwaninger M

Abstract

In ischemic stroke, the necrotic core is surrounded by a zone of inflammation, in which delayed cell death aggravates the initial insult. Here, we provide evidence that the receptor for advanced glycation end products (RAGE) functions as a sensor of necrotic cell death and contributes to inflammation and ischemic brain damage. The RAGE ligand high mobility group box 1 (HMGB1) was elevated in serum of stroke patients and was released from ischemic brain tissue in a mouse model of cerebral ischemia. A neutralizing anti-HMGB1 antibody and HMGB1 box A, an antagonist of HMGB1 at the receptor RAGE, ameliorated ischemic brain damage. Interestingly, genetic RAGE deficiency and the decoy receptor soluble RAGE reduced the infarct size. In vitro, expression of RAGE in (micro)glial cells mediated the toxic effect of HMGB1. Addition of macrophages to neural cultures further enhanced the toxic effect of HMGB1. To test whether immigrant macrophages in the ischemic brain mediate the RAGE effect, we generated chimeric mice by transplanting RAGE(-/-) bone marrow to wild-type mice. RAGE deficiency in bone marrow-derived cells significantly reduced the infarct size. Thus, HMGB1-RAGE signaling links necrosis with macrophage activation and may provide a target for anti-inflammatory therapy in stroke.

MeSH Terms
Animals Animals, Newborn Antibodies/pharmacology Bone Marrow Transplantation/methods Brain Infarction/genetics,metabolism,physiopathology Brain Ischemia/genetics,metabolism,physiopathology Cell Death/genetics Cells, Cultured Encephalitis/genetics,metabolism,physiopathology Female HMGB1 Protein/antagonists & inhibitors,genetics,metabolism Humans Macrophages/drug effects,metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Microglia/drug effects,metabolism Necrosis/genetics,metabolism,physiopathology Nerve Degeneration/genetics,metabolism,physiopathology Receptor for Advanced Glycation End Products Receptors, Immunologic/genetics,metabolism Signal Transduction/drug effects,physiology Transplantation Chimera
Chemicals
Antibodies HMGB1 Protein Receptor for Advanced Glycation End Products Receptors, Immunologic
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Muhammad Sajjad
Pharmacological Institute, University of Heidelberg, 69120 Heidelberg, Germany.
Barakat Waleed
Pharmacological Institute, University of Heidelberg, 69120 Heidelberg, Germany.
Stoyanov Stoyan
Department of Internal Medicine, University of Heidelberg, 69120 Heidelberg, Germany.
Murikinati Sasidhar
Pharmacological Institute, University of Heidelberg, 69120 Heidelberg, Germany.
Yang Huan
Feinstein Institute for Medical Research, Manhasset, New York 11030.
Tracey Kevin J
Feinstein Institute for Medical Research, Manhasset, New York 11030.
Bendszus Martin
Department of Neuroradiology, University of Heidelberg, 69120 Heidelberg, Germany.
Rossetti Grazisa
HMGBiotech, 20133 Milan, Italy.
Nawroth Peter P
Department of Internal Medicine, University of Heidelberg, 69120 Heidelberg, Germany.
Bierhaus Angelika
Department of Internal Medicine, University of Heidelberg, 69120 Heidelberg, Germany.
Schwaninger Markus
Pharmacological Institute, University of Heidelberg, 69120 Heidelberg, Germany.
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.2435-08.2008
Published
2008-11-12
Pages
12023-12031
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC4597312
Subset
IM
Grants
NIGMS NIH HHS · R01 GM062508 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.2435-08.2008 PMC Full Text View journal details
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