title: DAMP signaling is a key pathway inducing immune modulation after brain injury.
abstract: Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We analyzed release of HMGB1 isoforms by mass spectrometry and investigated its inflammatory potency and signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and by pharmacological blockade. Our results indicate that the cytokine-inducing, fully reduced isoform of HMGB1 was released from the ischemic brain in the hyperacute phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key mechanism explaining the complex postischemic brain-immune interactions.
authors.affiliation: Department of Neurology, University Heidelberg, 69120 Heidelberg, Germany, Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany, Munich Cluster for Systems Neurology, 80336 Munich, Germany, Arthur.Liesz@med.uni-muenchen.de Roland.Veltkamp@imperial.nhs.uk.
authors.forename: Arthur
authors.initials: A
authors.lastname: Liesz
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dalpke
authors.affiliation: Department of Neurology, University Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Mracsko
authors.affiliation: MRC Centre for Drug Safety Science, Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany, Munich Cluster for Systems Neurology, 80336 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Roth
authors.affiliation: Department of Neurology, University Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Laboratory of Biomedical Sciences, Feinstein Institute for Medical Research, Manhasset, New York 11030.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Neurology, University Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Na
authors.affiliation: Department of Neurology, University Heidelberg, 69120 Heidelberg, Germany, Department of Physiology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir, 35340, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Akhisaroglu
authors.affiliation: Department of Internal Medicine, University Heidelberg, 69120 Heidelberg, Germany, and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Eigenbrod
authors.affiliation: Department of Internal Medicine, University Heidelberg, 69120 Heidelberg, Germany, and.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.affiliation: Laboratory of Biomedical Sciences, Feinstein Institute for Medical Research, Manhasset, New York 11030.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: Department of Neurology, University Heidelberg, 69120 Heidelberg, Germany, Division of Brain Sciences, Imperial College London, London SW7 2AZ, United Kingdom Arthur.Liesz@med.uni-muenchen.de Roland.Veltkamp@imperial.nhs.uk.
authors.forename: Roland
authors.initials: R
authors.lastname: Veltkamp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D020521:Stroke / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D020033:Protein Isoforms; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
keywords: HMGB1; RAGE; alarmins; immunomodulation; myeloid-derived suppressor cell; stroke