Background:Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. This is mediated in part by granulopoiesis induced by the S100A8/A9-NLRP3-IL-1β signaling axis in injury-exposed neutrophils. Despite the transcriptional upregulation of the NLRP3 (Nod Like Receptor Family Pyrin Domain-Containing 3) inflammasome and associated signaling components in neutrophils, the serum levels of IL-1β (interleukin-1β), the effector molecule in granulopoiesis, were not affected by MI, suggesting that IL-1β is not released systemically. We hypothesize that IL-1β is released locally within the bone marrow (BM) by inflammasome-primed and reverse-migrating neutrophils.Methods:Using a combination of time-dependent parabiosis and flow cytometry techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in parabiotic mice by permanent ligation of the left anterior descending artery and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in noninfarcted parabionts. Last, using multiple neutrophil adoptive and BM transplant studies, we studied the molecular mechanisms that govern reverse migration and retention of the primed neutrophils, IL-1β secretion, and granulopoiesis. Cardiac function was assessed by echocardiography.Results:MI promoted greater accumulation of the inflammasome-primed neutrophils in the BM. Introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited their ability to stimulate granulopoiesis in the noninfarcted parabionts. Previous priming of the NLRP3 inflammasome is not a prerequisite, but the presence of a functional CXCR4 (C-X-C-motif chemokine receptor 4) on the primed-neutrophils and elevated serum S100A8/A9 levels are necessary for homing and retention of the reverse-migrating neutrophils. In the BM, the primed-neutrophils secrete IL-1β through formation of gasdermin D pores and promote granulopoiesis. Pharmacological and genetic strategies aimed at the inhibition of neutrophil homing or release of IL-1β in the BM markedly suppressed MI-induced granulopoiesis and improved cardiac function.Conclusions:Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (eg, IL-1β) directly at the sites of action rather through systemic release. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1β release.

中文翻译：

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NLRP3 炎症小体引发的中性粒细胞在骨髓中的保留对于心肌梗死诱导的粒细胞生成至关重要

背景：急性心肌梗死 (MI) 导致中性粒细胞过度产生和浸润到缺血心脏。这在一定程度上是由损伤暴露的中性粒细胞中 S100A8/A9-NLRP3-IL-1β 信号轴诱导的粒细胞生成介导的。尽管中性粒细胞中 NLRP3（Nod 样受体家族 Pyrin 结构域包含 3）炎症小体和相关信号成分的转录上调，但粒细胞生成中的效应分子 IL-1β（白细胞介素-1β）的血清水平不受 MI 的影响，表明 IL-1β 没有全身释放。我们假设 IL-1β 通过炎症小体引发和反向迁移的中性粒细胞在骨髓 (BM) 内局部释放。方法：结合使用时间依赖性共生和流式细胞术技术，我们首先描述了不同血细胞类型穿过联生屏障的迁移模式。接下来，我们通过永久结扎左前降支动脉在联生小鼠中诱导心肌梗死，并检查了损伤暴露的中性粒细胞渗透联生屏障并在未梗死的联生动物中诱导粒细胞生成的能力。最后，使用多项中性粒细胞过继和 BM 移植研究，我们研究了控制启动的中性粒细胞反向迁移和保留、IL-1β 分泌和粒细胞生成的分子机制。通过超声心动图评估心功能。结果：MI促进了BM中炎性体引发的中性粒细胞的更多积累。为中性粒细胞的自由运动引入时间依赖性联生屏障抑制了它们在未梗死的联生体中刺激粒细胞生成的能力。NLRP3 炎性体的先前启动不是先决条件，但启动的中性粒细胞上存在功能性 CXCR4（CXC 基序趋化因子受体 4）和升高的血清 S100A8/A9 水平对于反向迁移的中性粒细胞的归巢和保留是必需的. 在 BM 中，致敏的中性粒细胞通过形成 gasdermin D 孔分泌 IL-1β 并促进粒细胞生成。旨在抑制中性粒细胞归巢或 BM 中 IL-1β 释放的药理学和遗传策略显着抑制了 MI 诱导的粒细胞生成并改善了心脏功能。结论：我们的数据揭示了循环细胞如何通过在作用部位直接递送信号分子（例如 IL-1β）而不是通过全身释放在器官之间建立直接交流的新范例。我们认为该通路可能存在以限制全身 IL-1β 释放的脱靶效应。