Myeloid-mesenchymal crosstalk drives ARG1-dependent profibrotic metabolism via ornithine in lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung remodeling and collagen deposition that leads to respiratory failure. Myeloid cells are abundant in IPF lung and in murine lung fibrosis, but their functional effects are incompletely understood. Using mouse and human lung models, we show that ornithine produced by myeloid cells expressing arginase 1 (ARG1) serves as a substrate for proline and collagen synthesis by lung fibroblasts. The predominant ARG1-expressing myeloid cells in mouse lung were macrophages, but in IPF lung, high-dimensional imaging revealed ARG1 was expressed mainly in neutrophils. Small-molecule ARG1 inhibition suppressed both ornithine levels and collagen expression in cultured, precision-cut IPF lung slices and in murine lung fibrosis. These results were confirmed in macrophage-specific Arg1-KO mice. Furthermore, we found that this pathway is regulated by cell-to-cell crosstalk, starting with purinergic signaling: extracellular ATP receptor P2RX4 was necessary for fibroblast IL-6 expression, which, in turn, was necessary for ARG1 expression by myeloid cells. Taken together, our findings define an immune-mesenchymal circuit that governs profibrotic metabolism in lung fibrosis.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-08-28
DOI
https://doi.org/10.1172/jci188734
Citations
5
Primary Topic
Neonatal Respiratory Health Research
Type
article
Field-Weighted Citation Impact
7.59
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article

Myeloid-mesenchymal crosstalk drives ARG1-dependent profibrotic metabolism via ornithine in lung fibrosis

Walter L. Eckalbar, Tatsuya Tsukui, Trever G. Bivona, Dean Sheppard et al.
5 citations
Journal of Clinical Investigation
Neonatal Respiratory Health Research
7.59
article

Myeloid-mesenchymal crosstalk drives ARG1-dependent profibrotic metabolism via ornithine in lung fibrosis

Walter L. Eckalbar, Tatsuya Tsukui, Trever G. Bivona, Dean Sheppard, Aritra Bhattacharyya, Nivedita Biswas, Vincent C. Auyeung, Sixuan Pan, Hiroki Taenaka, Kaveh Boostanpour, K. C. Chang, Julia Nilsson, Satish K. Pillai, Javier Gómez Ortega, Paul J. Wolters, Prerna Dabral, Mallar Bhattacharya, Michael A. Matthay, Adam R. Abate, Whitney Tamaki, Kevin M. Tharp, Preeti Yadav, Lenka Maliskova, Ari B. Molofsky, Charles Chien, Arnab Ghosh, Rieko Muramatsu, Mazharul Maishan, Christopher Molina, Allon Wagner, Stanley Tamaki, Jun Wang, Baosheng Li, Xiaoyang Yin, Tanay Jujaray
article en
5 citations

Abstract

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung remodeling and collagen deposition that leads to respiratory failure. Myeloid cells are abundant in IPF lung and in murine lung fibrosis, but their functional effects are incompletely understood. Using mouse and human lung models, we show that ornithine produced by myeloid cells expressing arginase 1 (ARG1) serves as a substrate for proline and collagen synthesis by lung fibroblasts. The predominant ARG1-expressing myeloid cells in mouse lung were macrophages, but in IPF lung, high-dimensional imaging revealed ARG1 was expressed mainly in neutrophils. Small-molecule ARG1 inhibition suppressed both ornithine levels and collagen expression in cultured, precision-cut IPF lung slices and in murine lung fibrosis. These results were confirmed in macrophage-specific Arg1-KO mice. Furthermore, we found that this pathway is regulated by cell-to-cell crosstalk, starting with purinergic signaling: extracellular ATP receptor P2RX4 was necessary for fibroblast IL-6 expression, which, in turn, was necessary for ARG1 expression by myeloid cells. Taken together, our findings define an immune-mesenchymal circuit that governs profibrotic metabolism in lung fibrosis.

Journal of Clinical InvestigationVol. 135(21)
Berkeley College (US), Sanden (Japan) (JP), University of California, San Francisco (US), Discovery Institute (US), Pacific Research Institute (US), Shandong Tumor Hospital (CN), National Center of Neurology and Psychiatry (JP), University of California San Francisco Medical Center (US), Pulmonary and Allergy Associates (US), Chan Zuckerberg Initiative (United States) (US), Twist Bioscience (United States) (US), Vitalant (US), La Jolla Bioengineering Institute (US), Shandong First Medical University (CN), UCSF Helen Diller Family Comprehensive Cancer Center (US), Indian Statistical Institute (IN), University of California, Berkeley (US)
Openalex Percentile: Top 2%
Neonatal Respiratory Health Research
7.59
DOIOpen Access PDFOpenAlex
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