Innate immunity activation in the early brain injury period following subarachnoid hemorrhage

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.

Programmed Cell Deaths and Potential Crosstalk With Blood–Brain Barrier Dysfunction After Hemorrhagic Stroke

“…DL-3-n-Butylphthalide, a synthetic compound that has been approved for the treatment of ischemic stroke in China, has been shown to inhibit neurovascular inflammation via downregulation of intercellular adhesion molecule 1 (ICAM-1; . Despite a slight lag, it was recently revealed that these cytokines may also upregulate adhesion molecules, including ICAM-1, vascular adhesion molecule 1, and vascular adhesion protein 1 after hemorrhagic stroke (Ma et al, 2011;Xu et al, 2015;Cheng et al, 2018;Gris et al, 2019). These FIGURE 4 | Relationship among hemorrhagic stroke, programmed cell deaths, and blood-brain barrier (BBB) dysfunction.…”

“…Abbreviations: TNFα, tumor necrosis factor; IL-1α/1β/18, interleukin 1α/1β/18. recruited leukocytes further accumulate and transmigrate across the endothelium, finally releasing an abundance of cytokines and chemokines (Cheng et al, 2018;Gris et al, 2019). Cytokines mediating various signaling pathways are an important part of the inflammatory processes after hemorrhagic stroke.…”

Increased interleukin-6 levels in neuron-derived plasma small extracellular vesicles in patients with aneurysmal subarachnoid hemorrhage

“…Recently, researchers have found that EBI after SAH may be a leading factor contributing to unfavorable outcomes [4,5]. These findings suggest the importance of pathophysiologic mechanisms in the very early phase after aSAH, characterized by changes including microvascular filling defects, breakdown of ionic homeostasis, inflammation, and microarterial narrowing [6][7][8]. A reliable, early, economic and non-invasive approach is urgently in need to screen patients so as to improve prognosis .…”

“…There is substantial evidence that the inflammatory response occurs early after SAH and contributes to the progression of SAH-induced EBI [4,8,20]. Potential biomarkers have been studied, including interleukin-1α (IL-1α), IL-1β, IL-6, IL-8,IL-18, and tumor necrosis factor-alpha [21][22][23].…”

Increased Interleukin-6 Levels in Neuron-Derived Plasma Small Extracellular Vesicles of Subarachnoid Haemorrhage Patients

“…There is substantial evidence that the in ammatory response occured early after SAH and contributed to the progression of SAH-induced EBI [4,8,20]. Potential biomarkers that have been studied of in ammatory cytokines such as interleukin-1α(IL-1α), IL-1β, IL-6, IL-8,IL-18, and tumor necrosis factoralpha [21][22][23].…”