Abstract
Stroke is a leading cause of death and disability globally and is associated with a number of co-morbidities including sepsis and sickle cell disease (SCD). Despite thrombo-inflammation underlying these co-morbidities, its pathogenesis remains complicated and drug discovery programs aimed at reducing and resolving the detrimental effects remain a major therapeutic challenge. The objective of this study was to assess whether the anti-inflammatory pro-resolving protein Annexin A1 (AnxA1) was able to reduce inflammation-induced thrombosis and suppress platelet activation and thrombus formation in the cerebral microvasculature. Using two distinct models of pathological thrombo-inflammation (lipopolysaccharide (LPS) and sickle transgenic mice (STM)), thrombosis was induced in the murine brain using photoactivation (light/dye) coupled with intravital microscopy. The heightened inflammation-induced microvascular thrombosis present in these two distinct thrombo-inflammatory models was inhibited significantly by the administration of AnxA1 mimetic peptide AnxA1Ac2-26 (an effect more pronounced in the SCD model vs. the endotoxin model) and mediated by the key resolution receptor, Fpr2/ALX. Furthermore, AnxA1Ac2-26 treatment was able to hamper platelet aggregation by reducing platelet stimulation and aggregation (by moderating αIIbβ3 and P-selectin). These findings suggest that targeting the AnxA1/Fpr2/ALX pathway represents an attractive novel treatment strategy for resolving thrombo-inflammation, counteracting e.g., stroke in high-risk patient cohorts.
Highlights
Stroke is a leading cause of death and disability, with functional impairments producing significant losses in quality of life and accompanying financial burden [1,2,3]
Unregulated thrombo-inflammation, which involves a complex relationship between inflammatory leukocytes, platelets, and the vascular endothelium, is associated with a number of comorbidities such as sickle cell disease (“SCD” [7,8]) and infections, which predispose individuals to ischaemic stroke
In the context of an ischaemic stroke setting, we have previously shown that Annexin A1 (AnxA1)
Summary
Stroke is a leading cause of death and disability, with functional impairments producing significant losses in quality of life and accompanying financial burden [1,2,3]. The exact mechanisms responsible for post-ischaemic cerebral damage in stroke remain undefined, the intertwined processes of thrombosis and inflammation play crucial roles in the pathophysiology [4,5,6]. Unregulated thrombo-inflammation, which involves a complex relationship between inflammatory leukocytes (e.g., neutrophils), platelets, and the vascular endothelium, is associated with a number of comorbidities such as sickle cell disease (“SCD” [7,8]) and infections (e.g., sepsis [9,10]), which predispose individuals to ischaemic stroke. In the case of SCD, ~11% of SCD patients have a stroke before the age of 20, increasing to 24% by the age of 45 [11]. Cells 2020, 9, 2473 are more susceptible to bacterial infections, but infection itself is an independent risk factor for stroke and a major contributor to worse outcome post stroke, increasing recurrent stroke risk [4].
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