Aurora Semerano, MD
European Stroke Organisation Conference
September 1–3, 2021
Session: “Inflammation, Thrombosis and Stroke Pathogenesis,” September 3, 2021
The complex interplay between inflammation and thrombosis in ischemic stroke was the subject of the interesting scientific session chaired by Mervyn D. Vergouwen (Netherlands) and Christoph Kleinschnitz (Germany). The five speakers dissected the topic by presenting the main players involved in pathophysiology of stroke-related thrombo-inflammation, and prospected potential interventions of immune modulation.
Bernhard Nieswandt (Germany) showed how platelets, besides their well-established functions, have a critical role in inflammation. They are involved not only in the process of thrombus formation, but also in the subsequent mechanisms of infarct growth. Identifying the optimal target to interfere with platelet activity is crucial, due to the possible risk of hemorrhagic transformation. Two promising axes are discussed, namely the immunomodulatory function of von Willebrand Factor through its receptor on platelets Glycoprotein Ib, and the interplay with the kallikrein system and Factor XII activation. The resulting infiltration of immune cells (including T cells) into the ischemic brain contributes to the damage. Importantly, he pointed out that thrombo-inflammation doesn’t start after recanalization, but it is still ongoing during the occlusion, sustained by the collateral blood flow. This is supported in humans by a recent elegant work,1 which reported for the first time that leukocytes strongly accumulate in cerebral vessels distal to the occlusion. Bearing this in mind is fundamental to designing the optimal treatment.
Benoit Ho-Tin-Noé (France) focused on thrombosis in microvenules after arterial occlusion: Ischemic stroke may be seen as “an arterial disease with drastic venous consequences.” Microvascular inflammation and thrombosis affect the venous compartment and involve interactions between neutrophils, platelets and fibrinogen, being responsible for poor stroke outcome despite successful recanalization. Neutrophil margination is one of the earliest events leading to the downstream fibrin deposition and vessel micro-occlusion. Thrombolysis administration and hyperglycemia may have a role in modulating microthrombosis. Indeed, intravenous infusion of tPA improves microvascular patency in rats, and reduced markers of neutrophil activation are observed in thrombolysed stroke patients treated by EVT, whereas diabetes is able to prime the thromboinflammatory cascade. Early targeting of microvascular thombo-inflammation may help to maximize the benefits of endovascular thrombectomy.
María Angeles Moro (Spain) discussed the “other side of neutrophils” in stroke. Long considered detrimental in ischemic stroke, increasing evidence exists about neutrophil subpopulations with different characteristics, including neuroprotective features. The talk went deeper in analyzing neutrophil heterogeneity. She showed that, in preclinical studies, both the administration of rosiglitazone and the absence of TLR4 were associated with an increased infiltration of alternative neutrophils, endowed with cytoprotective properties, and characterized by a unique transcriptional profile. Interestingly, it has been recently recognized by the seminal contributions of Andrés Hidalgo and collegues2 that neutrophil heterogeneity is determined by the circadian rhythm, which also has a role in stroke pathophysiology. Skewing neutrophils toward neuroprotective phenotypes represents a promising goal for immune modulation in stroke medicine.
Costantino Iadecola (United States) talked about chronic microvascular dysfunction leading to cognitive impairment. Interestingly, Alzheimer pathology underlies a deep microvascular dysfunction, beside the well-known neuronal impairment. Mechanisms involving innate immune cells have been recently discovered. Indeed, beta amyloid can activate a receptor on resident meningeal and perivascular macrophages of the brain, which leads to free radical release and, ultimately, to endothelial dysfunction. Also, high dietary salt has been shown to be associated with cognitive impairment, independently from arterial hypertension. Immune cells at a distance are key players of the underlying pathogenetic mechanism: Indeed, specific T cells of the gut may release IL-17, which provokes endothelial dysfunction at the brain level, resulting in increased tau phosphorylation. In summary, evidence is provided that immune factors (both intrinsic and external to the brain) have a crucial role in microvascular dysfunction and cognitive impairment in the chronic setting.
E. Sander Connolly Jr. (United States) closed the session by discussing the role of the complement system in ischemic stroke. Preclinical studies suggest that the high rates of poor outcome despite successful recanalization may derive by a malignant progressive flow failure driven by the activation of the MBL pathway of the complement cascade, which is amplified by the alternative pathway, resulting in toxic downstream effectors C3a and C5a. Importantly, it is crucial to establish the optimal time window for intervention to maximize the beneficial effects when targeting the complement system, due to the involvement of C3a and C5a in tissue reorganization and repair in the subacute period. Efforts to trial safe and highly effective clinically approved small molecule inhibitors with a short duration of activity are likely to prove most successful in patients harboring cascade activating polymorphisms.
1 Kollikowski AM, Schuhmann MK, Nieswandt B, Müllges W, Stoll G, Pham M. Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke. Ann Neurol. 2020 Mar;87(3):466-479. doi: 10.1002/ana.25665.
2 Adrover JM, Del Fresno C, Crainiciuc G, Cuartero MI, Casanova-Acebes M, Weiss LA, Huerga-Encabo H, Silvestre-Roig C, Rossaint J, Cossío I, Lechuga-Vieco AV, García-Prieto J, Gómez-Parrizas M, Quintana JA, Ballesteros I, Martin-Salamanca S, Aroca-Crevillen A, Chong SZ, Evrard M, Balabanian K, López J, Bidzhekov K, Bachelerie F, Abad-Santos F, Muñoz-Calleja C, Zarbock A, Soehnlein O, Weber C, Ng LG, Lopez-Rodriguez C, Sancho D, Moro MA, Ibáñez B, Hidalgo A. A Neutrophil Timer Coordinates Immune Defense and Vascular Protection. Immunity. 2019 Feb 19;50(2):390-402.e10. doi: 10.1016/j.immuni.2019.01.002.