CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia.
CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia.
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DOI：
10.1186/s41232-023-00301-6
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发表时间：
2023-10-24
影响因子：
8.1
通讯作者：
中科院分区：
文献类型：
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作者：
补充氧气的早产儿患支气管肺发育不良（BPD）的风险很高，这是一种新生儿慢性肺部疾病。炎症伴巨噬细胞活化是BPD发病机制的核心。CXCL10是一种趋化和促炎趋化因子，在进化为BPD的婴儿肺部和高氧性BPD小鼠中升高。在这里，我们测试了CXCL10缺乏是否通过阻止巨噬细胞激活来保护新生儿高氧后的肺生长。为此，我们将Cxcl10敲除小鼠（Cxcl10−/−）和野生型小鼠暴露于高氧（85% O2）诱导的新生儿肺损伤和随后的再生实验模型中。此外，用CXCL10和/或CXCR3拮抗剂处理培养的原代人巨噬细胞和小鼠巨噬细胞（J744A.1）。我们的转录组学分析发现CXCL10是新生儿小鼠高氧后肺部炎症网络的中心枢纽。定量组织形态学分析显示，Cxcl10 - / -小鼠在一定程度上免受肺泡减少的影响。这些发现与Cxcl10 - / -小鼠在急性损伤和再生过程中弹性纤维的空间分布保持、胶原沉积减少以及巨噬细胞招募/浸润到肺部的保护有关。此外，对培养的人和小鼠巨噬细胞的研究表明，高氧诱导Cxcl10表达，进而通过CXCR3触发巨噬细胞的m1样活化和迁移。最后，我们证实了BPD婴儿肺中巨噬细胞相关的CXCL10的时间性增加。总之，我们的数据表明，实验和临床BPD中巨噬细胞来源的CXCL10通过CXCR3驱动巨噬细胞趋化，导致促纤维化肺重塑和肺泡化停止。因此，靶向CXCL10-CXCR3轴可能为BPD提供新的治疗途径。在线版本包含补充材料，可在10.1186/s41232-023-00301-6获得。
Preterm infants with oxygen supplementation are at high risk for bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Inflammation with macrophage activation is central to the pathogenesis of BPD. CXCL10, a chemotactic and pro-inflammatory chemokine, is elevated in the lungs of infants evolving BPD and in hyperoxia-based BPD in mice. Here, we tested if CXCL10 deficiency preserves lung growth after neonatal hyperoxia by preventing macrophage activation. To this end, we exposed Cxcl10 knockout (Cxcl10−/−) and wild-type mice to an experimental model of hyperoxia (85% O2)-induced neonatal lung injury and subsequent regeneration. In addition, cultured primary human macrophages and murine macrophages (J744A.1) were treated with CXCL10 and/or CXCR3 antagonist. Our transcriptomic analysis identified CXCL10 as a central hub in the inflammatory network of neonatal mouse lungs after hyperoxia. Quantitative histomorphometric analysis revealed that Cxcl10−/− mice are in part protected from reduced alveolar. These findings were related to the preserved spatial distribution of elastic fibers, reduced collagen deposition, and protection from macrophage recruitment/infiltration to the lungs in Cxcl10−/− mice during acute injury and regeneration. Complimentary, studies with cultured human and murine macrophages showed that hyperoxia induces Cxcl10 expression that in turn triggers M1-like activation and migration of macrophages through CXCR3. Finally, we demonstrated a temporal increase of macrophage-related CXCL10 in the lungs of infants with BPD. In conclusion, our data demonstrate macrophage-derived CXCL10 in experimental and clinical BPD that drives macrophage chemotaxis through CXCR3, causing pro-fibrotic lung remodeling and arrest of alveolarization. Thus, targeting the CXCL10-CXCR3 axis could offer a new therapeutic avenue for BPD. The online version contains supplementary material available at 10.1186/s41232-023-00301-6.
DOI：
10.1084/jem.20100098
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Zhou J;Tang PC;Qin L;Gayed PM;Li W;Skokos EA;Kyriakides TR;Pober JS;Tellides G
通讯作者：
Tellides G