Abstract
BackgroundAneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Inflammation is induced following SAH, but the exact role and phenotype of innate immune cells remain poorly characterized. We investigated the inflammatory components of the early brain injury in an animal model and in SAH patients.MethodSAH was induced through injection of blood in the subarachnoid space of C57Bl/6 J wild-type mice. Prospective blood collections were obtained at 12 h, days 1, 2, and 7 to evaluate the systemic inflammatory consequences of SAH by flow cytometry and enzyme-linked immunosorbent-assay (ELISA). Brains were collected, enzymatically digested, or fixed to characterize infiltrating inflammatory cells and neuronal death using flow cytometry and immunofluorescence. Phenotypic evaluation was performed at day 7 using the holding time and footprint tests. We then compared the identified inflammatory proteins to the profiles obtained from the plasma of 13 human SAH patients.ResultsFollowing SAH, systemic IL-6 levels increased rapidly, whereas IL-10 levels were reduced. Neutrophils were increased both in the brain and in the blood reflecting local and peripheral inflammation following SAH. More intracerebral pro-inflammatory monocytes were found at early time points. Astrocyte and microglia activation were also increased, and mice had severe motor deficits, which were associated with an increase in the percentage of caspase-3-positive apoptotic neurons. Similarly, we found that IL-6 levels in patients were rapidly increased following SAH. ICAM-1, bFGF, IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes. Moreover, high levels of Flt-1 and VEGF at admission were associated with worse outcomes.ConclusionSAH induces an early intracerebral infiltration and peripheral activation of innate immune cells. Furthermore, microglia and astrocytic activation are present at later time points. Our human and mouse data illustrate that SAH is a systemic inflammatory disease and that immune cells represent potential therapeutic targets to help this population of patients in need of new treatments.
Highlights
Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors
ICAM-1, Basic fibroblast growth factor (bFGF), IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes
SAH induces a peripheral and systemic inflammatory response To decipher the early inflammatory innate response present in our model, we first characterized the activation of peripheral cellular inflammation after SAH with
Summary
Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Innate cells have been inconsistently involved in the immune response following SAH [11,12,13,14,15] These studies suggest that cellular inflammation is activated during EBI and may be important in DCI. Our objectives were to characterize the inflammatory-like events (referred to as inflammation from hereon) during EBI and the associated neuronal cell death and motor functions in a mouse model of induced SAH by the following [1]: Measuring the blood cytokine response and leukocyte activation, brain monocytes, neutrophil infiltration, and microglia and astrocytic activation at multiple time points following SAH [2]; assess caspase-3 activation and cell death in neurons; and [3] assess motor function. We compared measures of the blood cytokine response in our murine model of SAH to blood inflammatory protein profiles in adult patients with SAH in a prospectively enrolled cohort from our critical care unit
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