Thromboinflammatory challenges in stroke pathophysiology

Abstract

Despite years of encouraging translational research, ischemic stroke still remains as one of the highest unmet medical needs nowadays, causing a tremendous burden to health care systems worldwide. Following an ischemic insult, a complex signaling pathway emerges leading to highly interconnected thrombotic as well as neuroinflammatory signatures, the so-called thromboinflammatory cascade. Here, we thoroughly review the cell-specific and time-dependent role of different immune cell types, i.e., neutrophils, macrophages, T and B cells, as key thromboinflammatory mediators modulating the neuroinflammatory response upon stroke. Similarly, the relevance of platelets and their tight crosstalk with a variety of immune cells highlights the relevance of this cell-cell interaction during microvascular dysfunction, neovascularization, and cellular adhesion. Ultimately, we provide an up-to-date overview of therapeutic approaches mechanistically targeting thromboinflammation currently under clinical translation, especially focusing on phase I to III clinical trials.

Systemic-inflammatory indices and clinical outcomes in patients with anterior circulation acute ischemic stroke undergoing successful endovascular thrombectomy

“…The thromboinflammatory response has been observed in all phases of AIS [ [13] , [14] , [15] ]. Importantly, this process can also occur in patients who initially achieve successful mechanical recanalization, potentially leading to secondary tissue damage and exacerbating stroke outcomes [ 14 , 36 , 37 ].…”

“…Inflammatory and thrombotic responses to acute cerebral ischemia and subsequent recanalization, known as thromboinflammation, are a key contributor to the occurrence and development of both early and long-term adverse outcomes [ [13] , [14] , [15] ]. Neutrophils and monocytes serve as mediators of innate immune and inflammatory responses, while lymphocytes are involved in adaptive immune responses [ [15] , [16] , [17] , [18] ]. These immune cells have been extensively studied in the context of AIS.…”

“…These immune cells have been extensively studied in the context of AIS. It is generally understood that neutrophils and monocytes have a deleterious effect, while lymphocytes primarily exert a protective role in AIS prognosis [ [15] , [16] , [17] , [18] ]. Additionally, platelets have been shown to regulate hemostasis, thrombosis, and inflammation [ 19 ].…”

Perspective from single‐cell sequencing: Is inflammation in acute ischemic stroke beneficial or detrimental?

“…In addition, although drugs targeting the mechanisms of ischemic brain injury have been identified in experimental stroke models, clinical trials have not yielded the same positive results as those seen in animal studies 182 . Clinical translation in the field of ischemic stroke is fraught with difficulties 183,184 . On the one hand, it may be due to the gap in animal models.…”

“… 182 Clinical translation in the field of ischemic stroke is fraught with difficulties. 183 , 184 On the one hand, it may be due to the gap in animal models. The current main experimental animal is rats.…”