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The HMGB1 Receptor RAGE Mediates Ischemic Brain Damage

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The HMGB1 Receptor RAGE Mediates Ischemic Brain Damage The Journal of Neuroscience, November 12, 2008 • 28(46):12023–12031 • 12023 Neurobiology of Disease The HMGB1 Receptor RAGE Mediates Ischemic Brain Damage Sajjad Muhammad,1* Waleed Barakat,1* Stoyan Stoyanov,2 Sasidhar Murikinati,1 Huan Yang,4 Kevin J. Tracey,4 Martin Bendszus,3 Grazisa Rossetti,5 Peter P. Nawroth,2 Angelika Bierhaus,2 and Markus Schwaninger1 1Pharmacological Institute, and Departments of 2Internal Medicine and 3Neuroradiology, University of Heidelberg, 69120 Heidelberg, Germany, 4Feinstein Institute for Medical Research, Manhasset, New York 11030, and 5HMGBiotech, 20133 Milan, Italy 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 immi- grant macrophages in the ischemic brain mediate the RAGE effect, we generated chimeric mice by transplanting RAGE Ϫ/Ϫ 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. Key words: RAGE; HMGB1; microglia; cerebral ischemia; stroke; macrophage Introduction that the receptor for advanced glycation end products (RAGE) and Stroke is the second most common cause of death worldwide. its ligand high mobility group box 1 (HMGB1) qualify for a role as Despite this, the only treatment of ischemic stroke available is mediators of ischemic inflammation and neurodegeneration. recanalization of the occluded vessel by thrombolysis. Throm- HMGB1 is a ubiquitous and abundant nuclear protein that is bolysis is safe and effective only within3hoftheonset of symp- released from necrotic and inflammatory cells and induces an toms. This short time window results in a low treatment rate and inflammatory response (Lotze and Tracey, 2005). It binds to warrants safer treatment regimes. In stroke, energy depletion RAGE and apparently also to toll-like receptor (TLR)2 and TLR4. leads to necrotic cell death in the most severely affected area of HMGB1 contains two DNA binding domains (box A and box B) ischemia. However, pathology may spread to the so-called pen- and an acidic C-terminal tail (see Fig. 2D). Box A acts as a specific umbra. In the penumbra, ischemia itself is not sufficiently severe antagonist for the interaction between HMGB1 and RAGE (Bi- to cause cell death. Toxic factors from the core of the lesion may anchi and Manfredi, 2007). RAGE is a member of the Ig super- pose an additional risk for cells in the penumbra. One such factor family of cell surface receptors (Bierhaus et al., 2005) that is acti- is spreading depression, which has been shown to promote the vated by several ligands including HMGB1 but also by advanced enlargement of ischemic lesions (Takano et al., 2007). In addi- glycation end products (AGEs), S100 proteins, and amyloid ␤ ␤ tion, soluble mediators from the necrotic core area may diffuse to -peptide (A ). In the brain, RAGE is present on neurons, glia, the adjacent penumbra and elicit a delayed inflammatory response and endothelial cells (Yan et al., 1996; Deane et al., 2003; Arancio that contributes to neuronal cell death. Here, we provide evidence et al., 2004; Bierhaus et al., 2004). However, the role of RAGE in stroke has not been studied in detail. Received May 30, 2008; revised Sept. 8, 2008; accepted Sept. 29, 2008. This work was supported by a grant from the Landesstiftung (Network Aging Research) Baden-Wu¨rttemberg to Materials and Methods A.B. and M.S., the Deutsche Forschungsgemeinschaft (SFB 405), and the Hopp Stiftung to P.P.N. K.J.T. is consultant Subjects. Stroke patients and control subjects represent a randomly se- to Critical Therapeutics, which has sponsored research and license agreements with The Feinstein Institute for lected subgroup of a previous study (Inta et al., 2008). Control subjects Medical Research for patents related to inhibiting HMGB1. Grazisa Rossetti is employed by HMGBiotech, a company were age- and sex-matched to stroke patients. All subjects gave their providing HMGB1-related reagents. informed consent. This study was approved by the local ethics The authors declare competing financial interests. committee. *S.M. and W.B. contributed equally to this work. ELISA and real-time RT-PCR. To determine HMGB1 concentrations, Correspondence should be addressed to Dr. Markus Schwaninger, Pharmacological Institute, University of Heidelberg, we used an ELISA kit (Shino-test). The detection threshold of this assay is Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. E-mail: [email protected]. Ͻ Ͻ W. Barakat’s present address: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig Uni- 1 ng/ml. The between-assay coefficient of variation is 8%. Serum versity, 44519 Zagazig, Egypt. samples were stored at Ϫ80°C before measurement. DOI:10.1523/JNEUROSCI.2435-08.2008 We purified RNA from whole cortex of the ischemic hemisphere and Copyright © 2008 Society for Neuroscience 0270-6474/08/2812023-09$15.00/0 from whole blood using RNAPure (Peqlab) and Mouse RiboPure kit 12024 • J. Neurosci., November 12, 2008 • 28(46):12023–12031 Muhammad et al. • RAGE in Cerebral Ischemia (Ambion), respectively. After reverse transcription using the High Ca- Table 1. Characteristics of stroke patients and control subjects on admission pacity cDNA Archive kit (Applied Biosystems), we performed real-time Stroke Control PCR with the following Taqman assays on demand: HMGB1, patients subjects Mn00849805_gH; glucuronidase, Mm00446953_m1; hypoxanthine phosphoribosyl-transferase 1, Mm00446968_m1; and TATA box bind- Women, n 33 ing protein, Mm00446973_m1. Quantified results for HMGB1 cDNA Men, n 55 Ϯ Ϯ Ϯ were normalized to a mean value of the three house-keeping genes. For Age, mean SEM 66.3 5.9 65.1 5.6 measurement of RAGE cDNA, the Absolute Blue QPCR SYBR Green Risk factors, n Mix (Thermo Scientific) and the following primers were used: RAGE No risk factor 0 2 forward, 5Ј-ATT CAG CTG TTG GTT GAG CCT-3Ј, RAGE reverse, One risk factor 1 3 5Ј-CCA TCC TTT ATC CAG TGG ACC T-3Ј (amplicon length, 113 bp); Two risk factors 6 1 cyclophilin forward, 5Ј-AGG TCC TGG CAT CTT GTC CAT-3Ј, cyclo- Three or more risk factors 1 2 philin reverse, 5Ј-GAA CCG TTT GTG TTT GGT CCA-3Ј (amplicon Stroke classification, n length, 51 bp). Quantified results of RAGE cDNA were normalized to Large-vessel disease 3 cyclophilin. The purity of the amplified products was checked by the Cardioembolic disease 3 dissociation curve. Others 2 Immunohistochemistry and TUNEL staining. For immunohistochem- Rankin scale, median (range) 3 (2–6) istry, sections or cells were fixed in 4% paraformaldehyde (PFA) for 30 NIHSS, median (range) 4 (1–13) min. After blocking in 5% normal horse serum, 5% normal goat serum, Stroke subtype was classified according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria (Adams or 1% bovine serum albumin, the following primary antibodies were etal.,1993).Riskfactorswereatrialfibrillation,hypertension,hypercholesterinemia,andsmoking.NIHSS,National Institutes of Health Stroke Scale. applied: goat anti-RAGE antibody (1:200, AGE 001; Biologo), rabbit anti-Iba1 antibody (0.5 ␮g/ml, 019-19741; Wako), rat anti-CD11b (1:50, MCA 74GA; Serotec), mouse anti-NeuN (1:50, MAB377; Millipore), mouse anti-GFAP (1:50, s.c.-33673; Santa Cruz Biochemicals), rabbit Cell culture. Mixed glial cells were prepared from the brains of neonatal anti-HMGB1 (1:100) (Yang et al., 2004). Then, the cells or sections were (postnatal day 2) wild-type or RAGE Ϫ/Ϫ mice as has been described washed with PBS before the secondary antibodies were applied: Cy3- (Marriot et al., 1995). Cells were cultured in DMEM (PAA) containing conjugated donkey anti-goat antibody (1:200, 705-165-147; Jackson Im- L-glutamine (0.5 mM), 10% FCS (PAA), penicillin (100 IU/ml), and munoResearch Laboratories), alexa 488-conjugated donkey anti-rabbit streptomycin (100 ␮g/ml). Primary cortical neurons were prepared from (1:100, A21206; Invitrogen), alexa 488-conjugated donkey anti-rat (1: brains of embryonic (E16) Naval Medical Research Institute mice (Po- 100, A21208; Invitrogen), TRITC-conjugated goat anti-mouse (1:150, trovita et al., 2004). Neurons (200,000 per well) were either incubated in 115-025-003; Jackson ImmunoResearch Laboratories), alexa 488- Neurobasal medium (Invitrogen) supplemented with B27 (Invitrogen), conjugated donkey anti-mouse (1:100, A21202; Invitrogen), Cy3- L-glutamine (0.5 mM), penicillin (100 IU/ml), and streptomycin (100 conjugated goat anti-rabbit (1:100, 111-165-144; Jackson ImmunoRe- ␮g/ml) on poly-D-lysine (50 ␮g/ml) coated 24-well plates or in DMEM search Laboratories). Finally, sections or cells were mounted with 4Ј,6Ј- containing all supplements on top of confluent glial cells. Mouse perito- diamidino-2-phenylindole dihydrochloride (DAPI) (Vectashield; neal macrophages were prepared as described previously (Dory, 1989). Vector Laboratories) containing medium. Cells (400,000 per well) were plated on mixed neural cultures 24 h before For staining of rabbit anti-HMGB1 antibody, sections were fixed in stimulation with HMGB1. Mixed cultures were used 6 d after plating the acetone, treated with 1.5% hydrogen peroxide in methanol and incu- neurons, whereas pure cortical neurons were used on day 10 in vitro.
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