Lipocalin-2 as an Infection-Related Biomarker to Predict Clinical Outcome in Ischemic Stroke

Abstract

ObjectivesFrom previous data in animal models of cerebral ischemia, lipocalin-2 (LCN2), a protein related to neutrophil function and cellular iron homeostasis, is supposed to have a value as a biomarker in ischemic stroke patients. Therefore, we examined LCN2 expression in the ischemic brain in an animal model and measured plasma levels of LCN2 in ischemic stroke patients.MethodsIn the mouse model of transient middle cerebral artery occlusion (tMCAO), LCN2 expression in the brain was analyzed by immunohistochemistry and correlated to cellular nonheme iron deposition up to 42 days after tMCAO. In human stroke patients, plasma levels of LCN2 were determined one week after ischemic stroke. In addition to established predictive parameters such as age, National Institutes of Health Stroke Scale and thrombolytic therapy, LCN2 was included into linear logistic regression modeling to predict clinical outcome at 90 days after stroke.ResultsImmunohistochemistry revealed expression of LCN2 in the mouse brain already at one day following tMCAO, and the amount of LCN2 subsequently increased with a maximum at 2 weeks after tMCAO. Accumulation of cellular nonheme iron was detectable one week post tMCAO and continued to increase. In ischemic stroke patients, higher plasma levels of LCN2 were associated with a worse clinical outcome at 90 days and with the occurrence of post-stroke infections.ConclusionsLCN2 is expressed in the ischemic brain after temporary experimental ischemia and paralleled by the accumulation of cellular nonheme iron. Plasma levels of LCN2 measured in patients one week after ischemic stroke contribute to the prediction of clinical outcome at 90 days and reflect the systemic response to post-stroke infections.

Measuring non‐polyaminated lipocalin‐2 for cardiometabolic risk assessment

“…Circulating lipocalin-2 is filtered in the kidney by the glomeruli, while the protein is captured by the proximal tubular epithelial cells. 30,31 Thus, when injected into the circulation, exogenous lipocalin-2 is enriched in the proximal tubule but does not appear in the urine in large quantities. 26 This is in line with the present findings that serum and urinary lipocalin-2 levels are not significantly correlated with each other in healthy human subjects.…”

Lipocalin‐2: Its perspectives in brain pathology and possible roles in cognition

“…However, this up‐regulation was a reversible effect. In rats with traumatic brain injury and transient focal cerebral ischaemia, LCN2 mRNA was significantly up‐regulated during 24 to 72 hours, although it was decreased 1 week or 1 month after injury . These findings imply that LCN2 can be acutely produced and released in the brain after an injury but then decreases after a period of time …”

“…Plasma LCN2 levels were increased in later‐life depressed patients with cognitive disturbance and also in VaD patients . However, a study of stroke patients reported that higher infection rates in acute ischaemic stroke patients could lead to an elevation of circulating LCN2 levels . Another study conducted in VaD patients reported no differences in plasma and CSF LCN2 levels .…”

“…LCN2 in the brain tissue is up‐regulated in response to brain injuries in many models. Following brain injury, the expression of LCN2 and its receptors were increased in the hippocampus or insulted brain regions …”

“…In response to brain injuries from systemic inflammation, diabetes mellitus, dementia, stroke and traumatic brain injury, up‐regulation of both LCN2 mRNA and protein was reported. The earliest point of the up‐regulation was found to occur 1 hour after systemic inflammation .…”