Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia.
Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia.
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DOI：
10.1183/13993003.02248-2020
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Alejandre Alcazar MA
中科院分区：
文献类型：
--
作者：
Hirani D;Alvira CM;Danopoulos S;Milla C;Donato M;Tian L;Mohr J;Dinger K;Vohlen C;Selle J;V Koningsbruggen-Rietschel S;Barbarino V;Pallasch C;Rose-John S;Odenthal M;Pryhuber GS;Mansouri S;Savai R;Seeger W;Khatri P;Al Alam D;Dötsch J;Alejandre Alcazar MA
暴露于氧气中的早产儿有患支气管肺发育不良（BPD）的风险，其特征是肺生长停止。炎症是重要的，但机制仍然难以捉摸。在这里，我们研究了严重的临床和实验性BPD的炎症通路和治疗靶点。首先，转录组学分析与计算机细胞去卷积确定了肺内在的M1样驱动的细胞因子模式在新生小鼠高氧后。这些发现通过巨噬细胞调节趋化因子（Ccl 2、Ccl 7、Cxcl 5）和标记物（Il 6、Il 17 A、Mmp 12）的基因表达得到证实。其次，高氧激活的白细胞介素6（IL-6）/信号转导和转录激活因子3（STAT 3）信号转导在体内进行了测量，并与肺泡上皮II型细胞（ATII）的损失以及间充质标记物增加。Il 6缺失小鼠表现出保留的ATII存活、减少的肌成纤维细胞和改善的弹性纤维组装，从而使肺生长和保护肺功能成为可能。整体IL-6信号传导和IL-6反式信号传导的药理学抑制促进了高氧后的肺泡化和ATII存活。第三，高氧引发M1样极化，可能通过Krüppel样因子4;巨噬细胞的高氧条件培养基和IL-6受损的ATII增殖。最后，临床数据表明，巨噬细胞相关血浆细胞因子升高是潜在的生物标志物，可以识别接受氧气的婴儿患BPD的风险增加。此外，巨噬细胞来源的IL 6和活性STAT 3与BPD肺上皮细胞的损失有关。我们提出了一种新的IL-6介导的机制，高氧激活巨噬细胞在未成熟的肺，损害ATII稳态和破坏弹性纤维的形成，从而抑制肺生长。这些数据提供的证据表明，IL-6 trans-signaling可以提供一个创新的药理学靶点，使肺生长在严重的新生儿慢性肺部疾病。在临床和实验性BPD中，M1样巨噬细胞活化与IL-6/STAT 3轴相关。抑制巨噬细胞相关的IL-6信号转导促进实验性BPD中ATII存活和肺生长，作为早产儿的新疗法https://bit.ly/3AhF7GP
Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD. First, transcriptomic analysis with in silico cellular deconvolution identified a lung-intrinsic M1-like-driven cytokine pattern in newborn mice after hyperoxia. These findings were confirmed by gene expression of macrophage-regulating chemokines (Ccl2, Ccl7, Cxcl5) and markers (Il6, Il17A, Mmp12). Secondly, hyperoxia-activated interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signalling was measured in vivo and related to loss of alveolar epithelial type II cells (ATII) as well as increased mesenchymal marker. Il6 null mice exhibited preserved ATII survival, reduced myofibroblasts and improved elastic fibre assembly, thus enabling lung growth and protecting lung function. Pharmacological inhibition of global IL-6 signalling and IL-6 trans-signalling promoted alveolarisation and ATII survival after hyperoxia. Third, hyperoxia triggered M1-like polarisation, possibly via Krüppel-like factor 4; hyperoxia-conditioned medium of macrophages and IL-6-impaired ATII proliferation. Finally, clinical data demonstrated elevated macrophage-related plasma cytokines as potential biomarkers that identify infants receiving oxygen at increased risk of developing BPD. Moreover, macrophage-derived IL6 and active STAT3 were related to loss of epithelial cells in BPD lungs. We present a novel IL-6-mediated mechanism by which hyperoxia activates macrophages in immature lungs, impairs ATII homeostasis and disrupts elastic fibre formation, thereby inhibiting lung growth. The data provide evidence that IL-6 trans-signalling could offer an innovative pharmacological target to enable lung growth in severe neonatal chronic lung disease. M1-like macrophage activation is linked to IL-6/STAT3 axis in clinical and experimental BPD. Inhibition of macrophage-related IL-6 trans-signalling promotes ATII survival and lung growth in experimental BPD as a new therapy for preterm infants. https://bit.ly/3AhF7GP
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DOI：
10.4049/jimmunol.1302470
发表时间：
2014-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Le TT;Karmouty-Quintana H;Melicoff E;Le TT;Weng T;Chen NY;Pedroza M;Zhou Y;Davies J;Philip K;Molina J;Luo F;George AT;Garcia-Morales LJ;Bunge RR;Bruckner BA;Loebe M;Seethamraju H;Agarwal SK;Blackburn MR
通讯作者：
Blackburn MR
DOI：
10.1152/ajplung.00050.2006
发表时间：
2007-02-01
影响因子：
4.9
作者：
Alejandre-Alcazar, Miguel A.;Kwapiszewska, Grazyna;Morty, Rory E.
通讯作者：
Morty, Rory E.
影响因子：
32.4
作者：
Fielding, Ceri A.;Jones, Gareth W.;McLoughlin, Rachel M.;McLeod, Louise;Hammond, Victoria J.;Uceda, Javier;Williams, Anwen S.;Lambie, Mark;Foster, Thomas L.;Liao, Chia-Te;Rice, Christopher M.;Greenhill, Claire J.;Colmont, Chantal S.;Hams, Emily;Coles, Barbara;Kift-Morgan, Ann;Newton, Zarabeth;Craig, Katherine J.;Williams, John D.;Williams, Geraint T.;Davies, Simon J.;Humphreys, Ian R.;O'Donnell, Valerie B.;Taylor, Philip R.;Jenkins, Brendan J.;Topley, Nicholas;Jones, Simon A.
通讯作者：
Jones, Simon A.
影响因子：
4.8
作者：
Mohr, Jasmine;Voggel, Jenny;Alcazar, Miguel A. Alejandre
通讯作者：
Alcazar, Miguel A. Alejandre
影响因子：
6
作者：
Leary, Sean;Das, Pragnya;Bhandari, Vineet
通讯作者：
Bhandari, Vineet