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DAMP Signaling is a Key Pathway Inducing Immune Modulation after Brain Injury
Open accessAbstract
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 investigated the inflammatory potency of HMGB1 and its 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 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.
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“This concept originally references peripheral immune processes, such as sterile injury, but similar processes have been observed in the CNS, including ischemia (Liesz et al, 2015), and recently, psychological stress.”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as Liesz et al, 2015
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Metadata
- Authors
- Liesz, A., Dalpke, A., Mracsko, E., Roth, S., Zhou, W., Yang, H., Na, S.-Y., Akhisaroglu, M., Fleming, T., Eigenbrod, T., Nawroth, P. P., Tracey, K. J., & Veltkamp, R.
- Affiliations
- Heidelberg University (DE)
- LMU Klinikum (DE)
- Feinstein Institute for Medical Research (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-01-14
- Volume
- 35
- Issue
- 2
- Pages
- 583-598
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4293412
- OpenAlex
- W2128591402
- Cited by
- 334
- References
- 56
- Citations by year
- 2026: 25 · 2025: 23 · 2024: 24 · 2023: 26 · 2022: 39 · 2021: 31 · 2020: 31 · 2019: 33 · 2018: 32 · 2017: 16 · 2016: 33 · 2015: 21
- FWCI
- 27.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Deutsche Forschungsgemeinschaft (SFB1118)
- Medical Research Council (MR/L006758/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- HMGB1, RAGE, ischemic stroke, brain injury, sickness behavior, immunosuppression, suppressor cells, lymphopenia, cytokines
- MeSH terms
- Receptor for Advanced Glycation End Products, Adult, Aged, Aged, 80 and over, Animals, Bone Marrow, Female, Humans, Male, Mice, Inbred C57BL, Middle Aged, Receptors, Immunologic, Spleen, T-Lymphocytes, Signal Transduction, Case-Control Studies, Cytokines, Protein Isoforms, Infarction, Middle Cerebral Artery, Stroke, HMGB1 Protein, Mice
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