Targeting Neutrophil Extracellular Traps for Stroke Prognosis: A Promising Path

Abstract

Stroke has become the first cause of functional disability and one of the leading causes of mortality worldwide. Therefore, it is of crucial importance to develop accurate biomarkers to assess stroke risk and prognosis. Emerging evidence suggests that neutrophil extracellular trap (NET) levels may serve as a valuable biomarker to predict stroke occurrence and functional outcome. NETs are known to create a procoagulant state by serving as a scaffold for tissue factor (TF) and platelets inducing thrombosis by activating coagulation pathways and endothelium. A literature search was conducted in two databases (MEDLINE and Scopus) to trace all relevant studies published between 1 January 2016 and 31 December 2022, addressing the potential utility of NETs as a stroke biomarker. Only full-text articles in English were included. The current review includes thirty-three papers. Elevated NET levels in plasma and thrombi seem to be associated with increased mortality and worse functional outcomes in stroke, with all acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage included. Additionally, higher NET levels seem to correlate with worse outcomes after recanalization therapies and are more frequently found in strokes of cardioembolic or cryptogenic origin. Additionally, total neutrophil count in plasma seems also to correlate with stroke severity. Overall, NETs may be a promising predictive tool to assess stroke severity, functional outcome, and response to recanalization therapies.

The Role of Neutrophils in Multiple Sclerosis and Ischemic Stroke

“…Recent results suggest that alterations in neutrophil function precede stroke onset rather than just being the effect of disease development, which may be the major difference in the role of neutrophils in the pathology of MS and stroke [97,98]. Moreover, the role of neutrophils and NETs in clot formation and ischemia/reperfusion injury made them one of the main factors contributing to stroke development and its exacerbation [93,94,[182][183][184][185] (Figure 3). Therapy regarding neutrophil depletion or inhibition has not succeeded.…”

“…The work by Wang et al suggested that tPa directly induces NET formation under ischemic conditions [181]. NETs present in the thrombi were shown to complicate their dissolution and removal, resulting in worse clinical outcomes after recanalization therapies [182][183][184][185]. Abbasi et al showed that older thrombi (>4 h post-stroke onset) showed elevated levels of citrullinated histone H3 (the marker of NETs) and were stiffer, which makes them harder to dissolve by r-tPa [165].…”

A Comprehensive Review on the Role of Resting-State Functional Magnetic Resonance Imaging in Predicting Post-Stroke Motor and Sensory Outcomes

“…Lesion volume or lesion location, age, stroke severity, and comorbid factors may influence stroke outcomes [42][43][44][45][46][47][48], but even mild stroke severity is not enough to provide an accurate prediction of favorable outcomes [49]. Thus, novel prognostic biomarkers are crucial for the development of personalized recovery treatment strategies [50] and the amelioration of patients' and caregivers' quality of life [51].…”

A promising frontier: targeting NETs for stroke treatment breakthroughs

“…Furthermore, it was discovered that the subgroup of patients with diabetes and acute hyperglycaemia had substantially elevated levels of NETs compared to individuals without these conditions [ 58 ]. Additionally, the correlation between the cumulative count of serum neutrophils and the concentrations of plasma NET markers in individuals experiencing acute stroke is linked to the severity of the stroke, as indicated by the NHISS score and infarct size, and is associated with an unfavourable prognosis [ 59 ].…”

“…This modification enables targeted drug delivery to ischaemic lesions and facilitates controlled release. By regulating microglia, protecting the BBB, and promoting neuronal survival, C-Lipo/CA effectively mitigates the effects of ischaemia [ 59 ].…”