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.

Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

“…Previous studies show that HMGB1 increases in patients with ischemic stroke and correlates with the number of circulating leukocytes, 27 stroke severity (NIHSS score, infarct size), and inflammatory markers (TNF-a, IL-1, IL-6, MMP9). [28][29][30][31] These findings are consistent with our study whereby a decrease in let7i was associated with a rise in HMGB1 as well as an increase in inflammatory response, MMP9, and infarct size.…”

CD43Lo classical monocytes participate in the cellular immune response to isolated primary blast lung injury

“…Alongside marked changes in circulating cells, we found a rapid and significant increase in CD43Lo/His48Hi monocyte-macrophages at 1hr in the lung compared to shams ( Figure 4A, B), which had all but subsided by 6hr. This increase could be in part due to an accelerated recruitment by cytokines and chemokines such as CINC-1, MIP-2 and enhanced ICAM-1 expression 18,34,36,37 or damage products 41 , which we found raised in the plasma at 6hr of PBLI rats (data not shown). There was a significant increase in CD43Lo/His48Hi monocyte-macrophages at 3hr in the BALF supporting our correlate findings in the lung, together with significant increases at 3 and 6hr in the monocyte-macrophage chemoattractant MCP-1.…”

Lymphocytopenia Is an Independent Predictor of Unfavorable Functional Outcome in Spontaneous Intracerebral Hemorrhage

“…10 These patients may represent a subgroup of patients potentially benefitting from immunomodulatory treatment approaches. 11 This study investigated for the first time in a large cohort of solely ICH patients (1) the natural course of lymphocytopenia, (2) parameters associated with LOA and during hospital stay, and (3) evaluated the clinical impact of lymphocytopenia both on admission and during clinical course on mortality and functional outcome.…”