The HMGB1 receptor RAGE mediates ischemic brain damage.
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.
Muhammad
Sajjad
S
Pharmacological Institute, University of Heidelberg, 69120 Heidelberg, Germany.
Barakat
Waleed
W
Pharmacological Institute, University of Heidelberg, 69120 Heidelberg, Germany.
Stoyanov
Stoyan
S
Department of Internal Medicine, University of Heidelberg, 69120 Heidelberg, Germany.
Murikinati
Sasidhar
S
Pharmacological Institute, University of Heidelberg, 69120 Heidelberg, Germany.
Yang
Huan
H
Feinstein Institute for Medical Research, Manhasset, New York 11030.
Tracey
Kevin J
KJ
Feinstein Institute for Medical Research, Manhasset, New York 11030.
Bendszus
Martin
M
Department of Neuroradiology, University of Heidelberg, 69120 Heidelberg, Germany.
Rossetti
Grazisa
G
HMGBiotech, 20133 Milan, Italy.
Nawroth
Peter P
PP
Department of Internal Medicine, University of Heidelberg, 69120 Heidelberg, Germany.
Bierhaus
Angelika
A
Department of Internal Medicine, University of Heidelberg, 69120 Heidelberg, Germany.
Schwaninger
Markus
M
Pharmacological Institute, University of Heidelberg, 69120 Heidelberg, Germany.
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000379:methods; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018183:Transplantation Chimera
D000906:Antibodies; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic