Intracerebral haemorrhage (ICH) is a severe form of stroke caused by spontaneous blood vessel rupture and bleeding into the brain tissue, resulting in significant disability and death. Our research, using in vitro systems, post-mortem brain tissue, zebrafish, and mouse models, has identified Cholesterol 25-hydroxylase (Ch25h) as a critical molecule influencing both the risk of ICH and the brain’s response to injury after a bleed.
Systemic infections and inflammation can compromise neurovascular integrity, increasing the risk of blood vessel rupture and ICH in some people (1). While infection-induced hypertension and endothelial dysfunction are known contributors, hypocholesterolemia—low levels of LDL cholesterol—is a less understood but clinically relevant risk factor (2). Cells respond to infection by temporarily reducing cholesterol availability, which can impair the formation and function of adherens junctions and may destabilise the neuroendothelium (3, 4). We hypothesise that this infection-driven cholesterol dysregulation can, under certain conditions, lead to neurovascular instability and ICH.
After ICH occurs, the influx of blood into the brain triggers widespread inflammation and cellular damage. Reactive oxygen species, iron from haemoglobin breakdown, and cellular debris activate microglia and recruit peripheral leukocytes, amplifying injury. Cholesterol metabolism plays a dual role in this context: disrupted lipid handling can intensify inflammation, while efficient cholesterol clearance supports tissue repair. Cholesterol is also essential for membrane synthesis and remyelination, making its regulation a delicate balance between injury and recovery.
Ch25h is an enzyme that converts cholesterol into 25-hydroxycholesterol (25HC), an oxysterol involved in immune regulation. We found that antiviral signalling increases Ch25h expression in zebrafish and human foetal brain tissue, correlating with ICH risk. In brain endothelial cell cultures and zebrafish models, Ch25h and 25HC disrupt vascular integrity by remodelling cholesterol metabolism (5). This suggests a mechanistic link between infection, cholesterol dysregulation, and neurovascular dysfunction. As well as its role in ICH risk, Ch25h also influences recovery after brain haemorrhage. In both mouse and human brain, Ch25h is strongly upregulated in microglia and macrophages after ICH. Loss of Ch25h in mice worsens outcomes, while treatment with 25HC enhances blood clearance and improves acute recovery. We also show 25HC regulates lipid droplet accumulation in macrophages following phagocytosis of red blood cells, indicating a broader role in lipid handling during haematoma clearance.
In summary, Ch25h and its product 25HC are central to both the onset and resolution of ICH. They mediate neurovascular dysfunction during infection and regulate immune and lipid responses during brain injury and recovery. Targeting this pathway may offer new preventative and therapeutic strategies to reduce ICH risk and improve outcomes, respectively.