Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis.
Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis.
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DOI：
10.1161/circulationaha.121.056019
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发表时间：
2022-01-04
期刊：
影响因子：
37.8
通讯作者：
Nagareddy PR
中科院分区：
文献类型：
--
作者：
Sreejit G;Nooti SK;Jaggers RM;Athmanathan B;Ho Park K;Al-Sharea A;Johnson J;Dahdah A;Lee MKS;Ma J;Murphy AJ;Nagareddy PR
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。这部分由损伤暴露的中性粒细胞中S100 A8/A9-NLRP 3-IL-1β信号传导轴诱导的粒细胞生成介导。尽管中性粒细胞中NLRP 3炎性体和相关信号传导组分的转录上调，但IL-1β（粒细胞生成中的效应分子）的血清水平不受MI影响，表明IL-1β不全身释放。我们假设IL-1β通过炎性小体引发和反向迁移的中性粒细胞在骨髓（BM）内局部释放。使用时间依赖性联体和流式细胞术技术的组合，我们首先表征了不同血细胞类型跨越联体屏障的迁移模式。接下来，我们通过永久结扎LAD动脉在联体小鼠中诱导MI，并检查损伤暴露的中性粒细胞渗透联体屏障和诱导非梗死联体中的粒细胞生成的能力。最后，利用多种中性粒细胞过继和骨髓移植研究，我们研究了控制致敏中性粒细胞的反向迁移和滞留、IL-1β分泌和粒细胞生成的分子机制。超声心动图评价心功能。MI促进BM中炎性小体引发的中性粒细胞的更大积聚。引入一个时间依赖性的共生屏障，中性粒细胞的自由运动抑制他们的能力，刺激非梗死的共生体的粒细胞生成。NLRP 3炎性体的预先引发不是先决条件，但是在引发的中性粒细胞上存在功能性CXCR 4（C-X-C基序趋化因子受体4）和升高的血清S100 A8/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BM中中性粒细胞归巢或IL-1β释放的药理学和/或遗传学策略显著抑制MI诱导的粒细胞生成，并改善心脏功能。我们的数据揭示了循环细胞如何通过传递信号分子（例如，IL-1β）直接作用于作用部位，而不是通过全身释放。我们认为，这一途径的存在可能限制了系统性IL-1β释放的脱靶效应。
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 inflammasome and associated signaling components in neutrophils, the serum levels of IL-1β, the effector molecule in granulopoiesis was not impacted 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. 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 LAD artery, and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in non-infarcted parabionts. Finally, utilizing 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. 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 non-infarcted parabionts. Prior 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/ or genetic strategies aimed at inhibition of neutrophil homing or release of IL-1β in the BM markedly suppressed MI-induced granulopoiesis and, improved cardiac function. Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (e.g., 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.