IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo
IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo
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DOI：
10.1164/rccm.201808-1599oc
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发表时间：
2019-07-15
影响因子：
24.7
通讯作者：
Walmsley, Sarah R.
中科院分区：
文献类型：
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作者：
Harris, Alison J.;Mirchandani, Ananda S.;Walmsley, Sarah R.
原理：急性呼吸窘迫综合征的定义是存在全身性缺氧，并随之发生紊乱性嗜酸性炎症。限制这种嗜酸性反应的持续时间和强度的局部机制仍然知之甚少。目的：为了验证在急性肺部炎症组织中产生促消退2型细胞因子的假设，（IL-4和IL-13）通过抑制HIF-1 α抑制缺氧的促炎作用（缺氧诱导因子-1 α）介导的中性粒细胞适应，导致肺损伤的解决。IL 4 Ra的神经细胞活化在人急性呼吸窘迫综合征患者样品中离体探索IL-4受体α信号传导途径，在缺氧条件下用重组IL-4体外培养人外周血中性粒细胞后，以及通过在竞争性嵌合体模型和用IL-4处理的野生型小鼠中研究IL-4 Ra缺陷型中性粒细胞的体内研究。测量和主要结果：急性呼吸窘迫综合征患者的人BAL中IL-4升高，其受体在患者血液中性粒细胞上被鉴定。用IL-4治疗人中性粒细胞抑制HIF-1 α依赖性缺氧存活和有限的促炎转录反应。在缺氧中增加的中性粒细胞凋亡，也观察到与IL-13，需要主动STAT信号，并依赖于氧敏感脯氨酰羟化酶PHD 2的表达。在体内，IL-4 Ra缺乏的中性粒细胞有一个生存的优势，在缺氧发炎的小生境;相反，发炎的肺治疗IL-4加速决议通过增加中性粒细胞apoptosis.Conclusions：我们描述了一个重要的相互作用，即IL-4 R α依赖的2型细胞因子信号转导可以直接抑制组织中的缺氧中性粒细胞的生存和促进解决嗜中性粒细胞介导的急性肺损伤。
Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1 alpha (hypoxia-inducible factor-1 alpha)-mediated neutrophil adaptation, resulting in resolution of lung injury.Methods: Neutrophil activation of IL4Ra (IL-4 receptor alpha) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4.Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1 alpha-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis.Conclusions: We describe an important interaction whereby IL4R alpha-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury.