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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.


Ruijuan Gao, Xueyan Peng, Carrighan Perry, Huanxing Sun, Aglaia Ntokou, Changwan Ryu, Jose L Gomez, Benjamin C Reeves, Anjali Walia, Naftali Kaminski, Nir Neumark, Genta Ishikawa, Katharine E Black, Lida P Hariri, Meagan W Moore, Mridu Gulati, Robert J Homer, Daniel M Greif, Holger K Eltzschig, Erica L Herzog. Macrophage-derived netrin-1 drives adrenergic nerve-associated lung fibrosis. The Journal of clinical investigation. 2021 Jan 04;131(1)

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PMID: 33393489

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