Abstract
SUMMARYSubarachnoid haemorrhage (SAH) is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated with brain injury after SAH in animals and patients, and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1) represents a possible therapeutic target. Here we report that a rupture of the middle cerebral artery in the rat produces heterogeneous infarct patterns similar to those observed in human SAH. Administration of the IL-1 receptor antagonist (IL-1Ra) reduced blood-brain barrier breakdown, and the extent of breakdown correlated with brain injury. After SAH, haem oxygenase-1 (HO-1) was strongly expressed around the bleed site and in the cortex and striatum, indicating the presence of free haem, a breakdown product of haemoglobin. HO-1 expression was also found in the same regions as microglial/macrophage expression of IL-1α. The direct effect of haem on IL-1α expression was confirmed in vitro using organotypic slice culture (OSC). Haem-induced cell death was dependent on IL-1 signalling, with IL-1Ra completely blocking cellular injury. Furthermore, stimulation of mouse primary mixed glial cells with haem induced the release of IL-1α, but not IL-1β. Thus, we suggest that haem, released from lysed red blood cells (RBCs) in the subarachnoid space, acts as a danger-associated molecular pattern (DAMP) driving IL-1-dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate therapeutic for the disease.
Highlights
Subarachnoid haemorrhage (SAH) is an acute injury to the brain with devastating consequences
IL-1 is produced by microglia/macrophages early after experimental SAH To assess the role that IL-1 played in driving acute brain injury after SAH we initially investigated whether it was produced after SAH in the rat
Our results indicate that both resting and fully activated microglia express IL-1, because expression was observed in cells of different morphology (Fig. 1)
Summary
Subarachnoid haemorrhage (SAH) is an acute injury to the brain with devastating consequences. Inflammation is strongly associated with brain injury after SAH: increases in leukocytes, platelets and serum C-reactive protein (CRP) levels correlate with poorer outcome (Frijns et al, 2006; Kasius et al, 2010; Rothoerl et al, 2006). Proinflammatory cytokines such as tumour necrosis factor- (TNF ), interleukin-8 (IL-8), high mobility group box-1 (HMGB-1) and IL6 are elevated in cerebral spinal fluid (CSF) of patients with a worse clinical grade (Fassbender et al, 2001; Nakahara et al, 2009; Schoch et al, 2007).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
