| First Author | Gao R | Year | 2021 |
| Journal | J Clin Invest | Volume | 131 |
| Issue | 1 | PubMed ID | 33393489 |
| Mgi Jnum | J:299984 | Mgi Id | MGI:6491834 |
| Doi | 10.1172/JCI136542 | Citation | Gao R, et al. (2021) Macrophage-derived netrin-1 drives adrenergic nerve-associated lung fibrosis. J Clin Invest 131(1) |
| abstractText | 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 alpha1 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 alpha1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced alpha1 blockers as a potentially new fibrotic therapy. |
