
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.09.611003
preprint
1
Article
A Nerve-Fibroblast Axis in Mammalian Lung Fibrosis
Ishikawa Genta http://orcid.org/0000-0002-8882-8288

Peng Xueyan http://orcid.org/0000-0002-0306-1082

McGovern John http://orcid.org/0009-0007-1310-3999

Ghincea Alexander http://orcid.org/0000-0001-7404-9921

Woo Samuel http://orcid.org/0000-0001-8991-0817

Okuno Daisuke
Yu Sheeline http://orcid.org/0009-0008-7650-7752

Lee Chris J.
Liu Angela
Saber Tina
Hu Buqu http://orcid.org/0000-0001-7233-987X

Sun Ying
Sun Huanxing http://orcid.org/0000-0003-2397-4652

Jumaily Karam Al http://orcid.org/0009-0005-0618-5151

Feghali-Bostwick Carol http://orcid.org/0000-0002-6750-6407

Sumida Tomokazu S. http://orcid.org/0000-0002-9806-2642

Sauler Maor http://orcid.org/0000-0001-5240-7978

Ryu Changwan
Herzog Erica L. http://orcid.org/0000-0002-7508-8575

09 9 2024
2024.09.09.611003https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.09.611003
nihpp-2024.09.09.611003.pdf
Tissue fibrosis contributes to pathology in vital organs including the lung. Curative therapies are scant. Myofibroblasts, pivotal effector cells in tissue fibrosis, accumulate via incompletely understood interactions with their microenvironment. In an investigative platform grounded in experimental lung biology, we find that sympathetic innervation stimulates fibrotic remodeling via noradrenergic α1-adrenergic receptor engagement in myofibroblasts. We demonstrate the anti-fibrotic potential of targeted sympathetic denervation and pharmacological disruption of noradrenergic neurotransmitter functions mediated by α1-adrenoreceptors (α1-ARs). Using the α1-adrenoreceptor subtype D as a representative α1-AR, we discover direct noradrenergic input from sympathetic nerves to lung myofibroblasts utilizing established mouse models, genetic denervation, pharmacologic interventions, a newly invented transgenic mouse line, advanced tissue mimetics, and samples from patients with diverse forms of pulmonary fibrosis. The discovery of this previously unappreciated nerve-fibroblast axis in the lung demonstrates the crucial contribution of nerves to tissue repair and heralds a novel paradigm in fibrosis research.
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