Institut national de la santé et de la recherche médicale (INSERM), EFS (Etablissement français du sang) Grand Est, BPPS (Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion) UMR (Unité mixte de recherche)-S1255, FMTS (Fédération de médecine translationnelle de Strasbourg), Université de Strasbourg, France (E.J.-B., N.R., L.M., C.M., S.M., F.L., B.H., P.H.M.).
Department of Medicine, Rush University Medical Center, Chicago, IL (J.R.).
Arterioscler Thromb Vasc Biol. 2024 Oct;44(10):2213-2222. doi: 10.1161/ATVBAHA.124.321104. Epub 2024 Aug 15.
Platelets prevent bleeding in a variety of inflammatory settings, the adhesion receptors and activation pathways involved being highly context-dependent and functionally redundant. In some situations, platelets recruited to inflammatory sites act independently of aggregation. The mechanisms underlying stable platelet adhesion in inflamed microvessels remain incompletely understood, in particular, whether and if so, how β1 and β3 integrins are involved.
The impact of isolated or combined platelet deficiency in β1 and β3 integrins on inflammation-associated hemostasis was investigated in 3 models of acute inflammation: immune complex-based cutaneous reverse passive Arthus reaction, intranasal lipopolysaccharide-induced lung inflammation, and cerebral ischemia-reperfusion following transient (2-hour) occlusion of the middle cerebral artery.
Mice with platelet-directed inactivation of (PF4Cre-β1) displayed no bleeding in any of the inflammation models, while mice defective in platelet (PF4Cre-β3) exhibited bleeding in all 3 models. Remarkably, the bleeding phenotype of PF4Cre-β3 mice was exacerbated in the reverse passive Arthus model by the concomitant deletion of β1 integrins, PF4Cre-β1/β3 animals presenting increased bleeding. Intravital microscopy in reverse passive Arthus experiments highlighted a major defect in the adhesion of PF4Cre-β1/β3 platelets to inflamed microvessels. Unlike PF4Cre-β1 and PF4Cre-β3 mice, PF4Cre-β1/β3 animals developed early hemorrhagic transformation 6 hours after transient middle cerebral artery occlusion. PF4Cre-β1/β3 mice displayed no more bleeding in lipopolysaccharide-induced lung inflammation than PF4Cre-β3 animals.
Altogether, these results show that the requirement for and degree of functional redundancy between platelet β1 and β3 integrins in inflammation-associated hemostasis vary with the inflammatory situation.
血小板在各种炎症环境中防止出血，涉及的粘附受体和激活途径高度依赖于背景，且具有功能冗余性。在某些情况下，募集到炎症部位的血小板独立于聚集而发挥作用。在炎症小血管中稳定血小板黏附的机制仍不完全清楚，特别是β1 和β3 整合素是否以及如何参与其中。
在 3 种急性炎症模型中研究了β1 和β3 整合素的血小板缺失对炎症相关止血的影响：基于免疫复合物的皮肤反向被动 Arthus 反应、鼻内脂多糖诱导的肺炎症和短暂（2 小时）大脑中动脉闭塞后的脑缺血再灌注。
PF4Cre-β1 定向血小板失活的小鼠在所有炎症模型中均无出血，而 PF4Cre-β3 血小板缺陷的小鼠在所有 3 种模型中均有出血。值得注意的是，PF4Cre-β3 小鼠的出血表型在反向被动 Arthus 模型中通过同时缺失β1 整合素而加重，PF4Cre-β1/β3 动物表现出增加的出血。反向被动 Arthus 实验中的活体显微镜检查突出显示了 PF4Cre-β1/β3 血小板与炎症小血管黏附的主要缺陷。与 PF4Cre-β1 和 PF4Cre-β3 小鼠不同，PF4Cre-β1/β3 动物在短暂性大脑中动脉闭塞后 6 小时发生早期出血性转化。PF4Cre-β1/β3 小鼠在脂多糖诱导的肺炎症中比 PF4Cre-β3 动物出血更多。
总之，这些结果表明血小板β1 和β3 整合素在炎症相关止血中的需求和功能冗余程度因炎症情况而异。
