Journal Article

Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis

Neumark, Nir, Hariri, Lida P., Ishikawa, Genta, Walia, Anjali, Black, Katharine E., Ryu, Changwan, Reeves, Benjamin C., Gomez, Jose L., Greif, Daniel M., Kaminski, Naftali, Eltzschig, Holger K., Herzog, Erica L., Sun, Huanxing, Homer, Robert J., Moore, Meagan W., Gao, Ruijuan, Perry, Carrighan, Peng, Xueyan, Ntokou, Aglaia, Gulati, Mridu

2021

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adrenergic mechanisms / Adrenergic nerves / Adrenergic receptors / Animals / Axon guidance / Biomedical research / Bleomycin / Bleomycin - adverse effects / Bleomycin - pharmacology / Collagen / Colorectal cancer / Colorectal carcinoma / Denervation / Development and progression / Extracellular matrix / Female / Fibroblasts / Fibrosis / Haploinsufficiency / Health aspects / Histology / Inflammation / Laminin / Lung - innervation / Lung - metabolism / Lung - pathology / Lung diseases / Lungs / Macrophages / Macrophages - metabolism / Macrophages - pathology / Male / Mice / Mice, Transgenic / Morphology / Nervous system / Netrin-1 / Netrin-1 - genetics / Netrin-1 - metabolism / Norepinephrine / Norepinephrine - genetics / Norepinephrine - metabolism / Physiological aspects / Pulmonary fibrosis / Pulmonary Fibrosis - chemically induced / Pulmonary Fibrosis - genetics / Pulmonary Fibrosis - metabolism / Pulmonary Fibrosis - pathology