{"doi":"10.1172/jci136542","title":"Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis","abstract":"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.","journal":"Journal of Clinical Investigation","year":2021,"id":149003,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":114,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":634143,"name":"Xueyan Peng","orcid":"0000-0002-0306-1082","position":1,"is_corresponding":false},{"id":634144,"name":"Carrighan Perry","orcid":"0000-0002-1289-027X","position":2,"is_corresponding":false},{"id":634145,"name":"Huanxing Sun","orcid":"0000-0003-2397-4652","position":3,"is_corresponding":false},{"id":580264,"name":"Aglaia Ntokou","orcid":"0000-0002-5272-580X","position":4,"is_corresponding":false},{"id":634146,"name":"Changwan Ryu","orcid":"0000-0001-6211-4327","position":5,"is_corresponding":false},{"id":79011,"name":"José L. Gómez","orcid":"0000-0002-6521-6318","position":6,"is_corresponding":false},{"id":240751,"name":"Benjamin C. Reeves","orcid":"0000-0002-5924-6991","position":7,"is_corresponding":false},{"id":634147,"name":"Anjali Walia","orcid":"0000-0003-1669-5532","position":8,"is_corresponding":false},{"id":12162,"name":"Naftali Kaminski","orcid":"0000-0001-5917-4601","position":9,"is_corresponding":false},{"id":106126,"name":"Nir Neumark","orcid":"0000-0002-5560-6136","position":10,"is_corresponding":false},{"id":634148,"name":"Genta Ishikawa","orcid":"0000-0002-8882-8288","position":11,"is_corresponding":false},{"id":303536,"name":"Katharine E. Black","orcid":null,"position":12,"is_corresponding":false},{"id":249897,"name":"Lida P. Hariri","orcid":"0000-0002-6190-624X","position":13,"is_corresponding":false},{"id":635374,"name":"Meagan W. Moore","orcid":null,"position":14,"is_corresponding":false},{"id":476891,"name":"Mridu Gulati","orcid":"0000-0002-4082-1351","position":15,"is_corresponding":false},{"id":41685,"name":"Robert Homer","orcid":"0000-0002-2055-5885","position":16,"is_corresponding":false},{"id":580265,"name":"Daniel M. Greif","orcid":"0000-0002-9842-3751","position":17,"is_corresponding":false},{"id":270716,"name":"Holger K. Eltzschig","orcid":"0000-0002-5676-6473","position":18,"is_corresponding":false},{"id":449354,"name":"Erica L. Herzog","orcid":"0000-0002-7508-8575","position":19,"is_corresponding":false},{"id":635373,"name":"Ruijuan Gao","orcid":null,"position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-18T23:42:51.282401Z","pmid":"33393489","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}