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Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction.
Circulation ( IF 35.5 ) Pub Date : 2020-01-16 , DOI: 10.1161/circulationaha.119.043833
Gopalkrishna Sreejit 1, 2 , Ahmed Abdel-Latif 3 , Baskaran Athmanathan 1, 2 , Rahul Annabathula 3 , Ashish Dhyani 2 , Sunil K Noothi 2, 4 , Gregory A Quaife-Ryan 5, 6 , Annas Al-Sharea 7 , Gerard Pernes 7 , Dragana Dragoljevic 7 , Hind Lal 8 , Kate Schroder 9, 10 , Beatriz Y Hanaoka 8, 11 , Chander Raman 8 , Maria B Grant 4 , James E Hudson 6 , Susan S Smyth 3 , Enzo R Porrello 12, 13 , Andrew J Murphy 7, 14 , Prabhakara R Nagareddy 1, 2
Affiliation  

BACKGROUND Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. METHODS Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI. RESULTS Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes. CONCLUSIONS Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.

中文翻译:

中性粒细胞衍生的 S100A8/A9 放大心肌梗塞后的粒细胞生成。

背景心肌梗塞(MI) 触发骨髓细胞生成,导致中性粒细胞的产生增加。然而,维持它们的产生和募集到受伤心脏的机制尚不清楚。方法使用左前降支永久结扎小鼠模型和流式细胞术,我们首先表征了 MI 对不同骨髓细胞类型的时间和空间影响。我们接下来对梗塞内不同类型的心脏细胞进行了全局转录组分析,以确定急性炎症反应的驱动因素和潜在的信号通路。使用遗传和药理学策略的组合,我们确定了导致 MI 诱导的骨髓细胞生成的事件的后遗症。通过超声心动图评估心脏功能。在一组急性心肌梗死患者中研究了中性粒细胞增多的早期指标与主要不良心血管事件的关联。结果 MI 的诱导导致中性粒细胞快速募集到梗塞,在那里它们释放特定的警报素 S100A8 和 S100A9。这些警报蛋白与 Toll 样受体 4 结合,并在幼稚的中性粒细胞中启动包含 3 个炎性体的 nod 样受体家族 pyrin 结构域,并促进白细胞介素 1β 的分泌。释放的白细胞介素 1β 与骨髓中造血干细胞和祖细胞上的受体(白细胞介素 1 受体 1 型)相互作用,并以细胞自主方式刺激粒细胞生成。旨在破坏 S100A8/A9 及其下游信号级联反应的遗传或药理学策略可抑制 MI 诱导的粒细胞生成并改善心脏功能。此外,在急性冠脉综合征患者中,入院时和血运重建后较高的中性粒细胞计数与主要不良心血管疾病结局呈正相关。结论 我们的研究为中性粒细胞衍生的警报蛋白 (S100A8/A9) 在决定心肌损伤后随后的炎症反应的性质方面的主要作用提供了新的证据。旨在破坏中性粒细胞中 S100A8/A9 信号传导或其下游介质(例如,包含 3 个炎性体、白细胞介素-1β 的 nod 样受体家族 pyrin 结构域)的治疗策略可抑制粒细胞生成并可能改善急性冠脉综合征患者的心功能。入院时和血运重建后较高的中性粒细胞计数与主要不良心血管疾病结果呈正相关。结论 我们的研究为中性粒细胞衍生的警报蛋白 (S100A8/A9) 在决定心肌损伤后随后的炎症反应的性质方面的主要作用提供了新的证据。旨在破坏中性粒细胞中 S100A8/A9 信号传导或其下游介质(例如,包含 3 个炎性体、白细胞介素-1β 的 nod 样受体家族 pyrin 结构域)的治疗策略可抑制粒细胞生成并可能改善急性冠脉综合征患者的心功能。入院时和血运重建后较高的中性粒细胞计数与主要不良心血管疾病结果呈正相关。结论 我们的研究为中性粒细胞衍生的警报蛋白 (S100A8/A9) 在决定心肌损伤后随后的炎症反应的性质方面的主要作用提供了新的证据。旨在破坏中性粒细胞中 S100A8/A9 信号传导或其下游介质(例如,包含 3 个炎性体、白细胞介素-1β 的 nod 样受体家族 pyrin 结构域)的治疗策略可抑制粒细胞生成并可能改善急性冠脉综合征患者的心功能。
更新日期:2020-03-30
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