Department of Pediatrics, School of Medicine, UCSD, San Diego, California, USA.
Thermo Fisher Scientific, Carlsbad, California, USA.
J Clin Invest. 2019 Jul 11;129(10):4091-4109. doi: 10.1172/JCI122258.
Persistent, unresolved inflammation in the liver represents a key trigger for hepatic injury and fibrosis in various liver diseases and is controlled by classically activated pro-inflammatory macrophages, while restorative macrophages of the liver are capable of reversing inflammation once the injury trigger ceases. Here we have identified a novel role for neutrophils as key contributors to resolving the inflammatory response in the liver. Using two models of liver inflammatory resolution, we found that mice undergoing neutrophil depletion during the resolution phase exhibited unresolved hepatic inflammation, activation of the fibrogenic machinery and early fibrosis. These findings were associated with an impairment of the phenotypic switch of pro-inflammatory macrophages into a restorative stage after removal of the cause of injury and an increased NLRP3 / miR-223 ratio. Mice with a deletion of the granulocyte specific miR-223 gene showed a similarly impaired resolution profile that could be reversed by restoring miR-223 levels using a miR-223 3p mimic or infusing neutrophils from wildtype animals. Collectively, our findings reveal a novel role for neutrophils in the liver as resolving effector cells that induce pro-inflammatory macrophages into a restorative phenotype, potentially via miR-223.
肝脏中持续存在、未解决的炎症是各种肝病肝损伤和纤维化的关键触发因素，由经典激活的促炎巨噬细胞控制，而肝脏的修复性巨噬细胞能够在损伤触发因素停止后逆转炎症。在这里，我们发现中性粒细胞在肝脏炎症反应的消退中起着关键作用。使用两种肝脏炎症消退模型，我们发现，在消退阶段进行中性粒细胞耗竭的小鼠表现出未解决的肝炎症、纤维发生机制的激活和早期纤维化。这些发现与损伤原因消除后促炎巨噬细胞向修复性阶段的表型转换受损以及 NLRP3/miR-223 比率增加有关。具有粒细胞特异性 miR-223 基因缺失的小鼠表现出类似的消退缺陷，可通过使用 miR-223 3p 模拟物恢复 miR-223 水平或输注来自野生型动物的中性粒细胞来逆转。总之，我们的研究结果揭示了中性粒细胞在肝脏中作为消退效应细胞的新作用，其可能通过 miR-223 将促炎巨噬细胞诱导为修复表型。
