Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
J Clin Invest. 2021 Jan 4;131(1). doi: 10.1172/JCI136542.
Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.
纤维化是一种巨噬细胞驱动的细胞外基质失控积累的过程。神经导向蛋白如 netrin-1 促进炎症性瘢痕形成。我们发现巨噬细胞衍生的 netrin-1 通过其神经元导向功能刺激纤维化。在小鼠中，吸入博来霉素引起的纤维化会产生表达 netrin-1 的巨噬细胞和成纤维细胞，重塑肾上腺素能神经，并增加去甲肾上腺素。细胞特异性敲除小鼠表明，胶原积累、纤维组织学和与神经相关的终点需要巨噬细胞而非成纤维细胞来源的 netrin-1。肾上腺素能神经切断术；netrin-1 的受体（结直肠癌缺失）的杂合不足；以及治疗性α1 肾上腺素能受体拮抗剂改善胶原含量和组织学。一项特发性肺纤维化 (IPF) 肺微阵列数据集显示 netrin-1 表达增加。IPF 肺组织富含 netrin-1+巨噬细胞和去甲肾上腺素。一项纵向 IPF 队列研究表明，接受 α1 肾上腺素能受体阻断治疗的患者生存率提高。这项工作表明，巨噬细胞通过 netrin-1 驱动的肾上腺素能过程刺激肺纤维化，并引入 α1 阻滞剂作为一种潜在的新的纤维化治疗方法。
