Eliminating the blood clot responsible for an ischemic stroke can improve a patient’s outcome, even save their life. But, the treatment—an intravenous dose of tissue plasminogen activator (rt-PA)—can only be given in the first few hours of symptoms. After that, the risk of hemorrhage associated with rt-PA is no longer offset by its benefits. Increased matrix metalloprotease 9 (MMP-9), which breaks down the blood-brain barrier matrix, is suspected to contribute to this risk, the enzyme being activated by both rt-PA and by LOX-1—a hypoxia-induced vascular endothelial protein. To investigate this possibility, Arkelius and colleagues induced stroke in rats and noted that indeed MMP-9 levels were increased after 6 hours and that levels of the enzyme correlated with LOX-1 expression. Similarly, in human cerebrovascular endothelial cells exposed to hypoxia and glucose starvation (to mimic stroke), MMP-9 levels rose by 3 hours. Importantly, in rats treated with rt-PA after stroke, additional LOX-1 and MMP-9 inhibition reduced the number and severity of hemorrhages, and better maintained neurological function compared with rt-PA alone. If such benefits translate to humans, clot destruction could become safer and have a longer treatment window, say the team.

Platelets have important immune functions during an infection. They release cytokines, engulf bacteria, and promote immune cell activity. But it appears they have an immune-suppressing role too. Platelet-lacking mice, for example, have more active inflammatory T cells than control counterparts. And, low platelet counts (thrombocytopenia) is often seen in patients with sepsis—an out of control immune response. To investigate platelets’ role in calming the innate immune system, Li et al studied monocytes and neutrophils from thrombocytopenic mice. While the neutrophils were largely unchanged, the monocytes produced more inflammatory cytokines in response to a bacterial toxin challenge than did monocytes from control animals. Moreover, if the thrombocytopenia was temporary, then once the platelet levels bounced back, monocyte cytokine production returned to normal. The team went on to show the platelets’s effect on monocytes was dependent on physical contact, mediated by surface protein CD47, and involved epigenetic regulation—the histone methylation status of inflammatory genes was altered in the monocytes. Importantly, the work confirms that thrombocytopenia independently drives immune dysfunction, which could ultimately lead to the design of better treatments for conditions like sepsis.

Andersen-Tawil syndrome (ATS1) is a rare inherited disorder with symptoms including, to a variable extent, muscle weakness, episodic paralysis, characteristic facial and skeletal anomalies and heart arrhythmia. The condition, which has no specific treatment, is commonly caused by mutation of the widely expressed potassium channel Kir2.1. Cruz and colleagues now report a new ATS1-causing Kir2.1 mutation and examine its pathological mechanism in mice. A mother suffering significant arrhythmias and her son with an irregular heart rhythm were found to carry the mutation—a cysteine to tyrosine switch (C122Y)—and the team used a vector based gene transfer technique to express the mutant protein in mice. The animals closely recapitulated the cardiac symptoms of the patients—altered conduction and heightened susceptibility to arrhythmia. Molecular analyses showed that while the protein could assemble into tetramers and traffic to membranes like the wild type protein, its interaction with phospholipid PIP₂—a Kir2.1 agonist that stabilizes channel opening—was disrupted, resulting in defective cardiomyocyte excitability. In providing insights into the molecular regulation of Kir2.1, the work may inform development of specialized treatments for ATS1 and potentially other arrhythmogenic diseases.

消除导致缺血性中风的血栓可以改善患者的预后，甚至挽救他们的生命。但是，治疗——静脉注射组织纤溶酶原激活剂（rt-PA）——只能在症状出现的最初几个小时内进行。此后，与 rt-PA 相关的出血风险不再与其益处相抵消。基质金属蛋白酶 9 (MMP-9) 会分解血脑屏障基质，怀疑会导致这种风险，该酶会被 rt-PA 和 LOX-1（一种缺氧诱导的血管内皮蛋白）激活。为了研究这种可能性，Arkelius 及其同事在大鼠中诱导中风，并指出 MMP-9 水平确实在 6 小时后增加，并且该酶的水平与 LOX-1 表达相关。同样，在暴露于缺氧和葡萄糖饥饿（模拟中风）的人脑血管内皮细胞中，MMP-9 水平上升了 3 小时。重要的是，在中风后接受 rt-PA 治疗的大鼠中，与单独使用 rt-PA 相比，额外的 LOX-1 和 MMP-9 抑制减少了出血的数量和严重程度，并且更好地维持了神经功能。研究小组表示，如果这种益处转化为人类，血栓破坏可能会变得更安全，并且治疗窗口期更长。

血小板在感染期间具有重要的免疫功能。它们释放细胞因子、吞噬细菌并促进免疫细胞活性。但它们似乎也具有免疫抑制作用。例如，缺乏血小板的小鼠比对照小鼠具有更活跃的炎症 T 细胞。而且，脓毒症患者经常出现低血小板计数（血小板减少症），这是一种失控的免疫反应。为了研究血小板在镇静先天免疫系统中的作用，Li 等人研究了血小板减少小鼠的单核细胞和中性粒细胞。虽然中性粒细胞基本没有变化，但与对照动物的单核细胞相比，单核细胞在应对细菌毒素攻击时产生了更多的炎性细胞因子。此外，如果血小板减少是暂时的，那么一旦血小板水平反弹，单核细胞细胞因子的产生就会恢复正常。研究小组继续表明，血小板对单核细胞的影响取决于表面蛋白 CD47 介导的物理接触，并涉及表观遗传调节——单核细胞中炎症基因的组蛋白甲基化状态发生了改变。重要的是，这项工作证实血小板减少症独立驱动免疫功能障碍，这最终可能导致设计出针对脓毒症等疾病的更好治疗方法。

Andersen-Tawil 综合征 (ATS1) 是一种罕见的遗传性疾病，其症状包括不同程度的肌肉无力、阵发性麻痹、特征性面部和骨骼异常以及心律失常。这种情况没有具体的治疗方法，通常是由广泛表达的钾通道 Kir2.1 突变引起的。 Cruz 及其同事现在报告了一种新的 ATS1 引起的 Kir2.1 突变，并在小鼠中检查了其病理机制。一位患有严重心律失常的母亲和她心律不齐的儿子被发现携带这种突变——半胱氨酸到酪氨酸的转换（C122Y）——研究小组使用基于载体的基因转移技术在小鼠中表达突变蛋白。这些动物密切地再现了患者的心脏症状——传导改变和心律失常的易感性增加。分子分析表明，虽然该蛋白可以像野生型蛋白一样组装成四聚体并运输到细胞膜，但它与磷脂 PIP ₂（一种稳定通道开放的 Kir2.1 激动剂）的相互作用被破坏，导致心肌细胞兴奋性缺陷。通过深入了解 Kir2.1 的分子调控，这项工作可能为 ATS1 和其他潜在致心律失常疾病的专门治疗方法的开发提供信息。