DAMP Signaling is a Key Pathway Inducing Immune Modulation after Brain Injury

• DOI: 10.1523/jneurosci.2439-14.2015
• Publication Date: 2015-01-14T17:43:24Z
• Authors: Arthur Liesz; Alexander Dalpke; Eva Mracsko; Stefan Roth; Wei Zhou; Huan Yang; Shin-Young Na; Mustafa Akhisaroglu; Thomas Fleming; Tatjana Eigenbrod; Peter P. Nawroth; Kevin J. Tracey; Roland Veltkamp
• Keywords: HMGB1; RAGE

Acute brain lesions induce profound alterations of the peripheral immune response comprising opposing phenomena early activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental ischemia as a paradigm acute additionally investigated large cohort stroke patients. inflammatory potency HMGB1 its pathways by immunological in vivo vitro techniques. Features complex behavioral sickness behavior syndrome were characterized homecage analysis. downstream signaling, particularly with RAGE, was studied various transgenic pharmacological blockade. Our results indicate that released from ischemic hyperacute phase mice Cytokines secreted periphery to injury induced behavior, which could be abrogated inhibition HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release bone marrow egress splenic proliferation marrow-derived suppressor cells, inhibiting adaptive responses vitro. Furthermore, resulted functional exhaustion mature monocytes lymphopenia, hallmarks suppression after extensive ischemia. This study introduces HMGB1-RAGE-mediated key mechanism explaining postischemic interactions.