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Editor’s note
Open Access | 
10.1172/JCI200729
Alveolar macrophage-fibroblast crosstalk includes a feedforward arginase 1/IL-6 circuit implicated in pulmonary fibrosis
G.R. Scott Budinger
Division of Pulmonary and Critical Care Medicine, and Simpson Querrey Lung Institute for Translational Science (SQ LIFTS), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Address correspondence to: G.R. Scott Budinger, Northwestern University Feinberg School of Medicine, Divisions of Thoracic Surgery, Pulmonary and Critical Care Medicine, 303 E. Superior, SQ-5-522, Chicago, Illinois 60611, USA. Email: s-buding@northwestern.edu.
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Published November 3, 2025 - More info
J Clin Invest. 2025;135(21):e200729. https://doi.org/10.1172/JCI200729.
© 2025 Budinger This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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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.
Authors
Preeti Yadav, Javier Gómez Ortega, Prerna Dabral, Whitney Tamaki, Charles Chien, Kai-Chun Chang, Nivedita Biswas, Sixuan Pan, Julia Nilsson, Xiaoyang Yin, Aritra Bhattacharyya, Kaveh Boostanpour, Tanay Jujaray, Jasper T. Wang, Tatsuya Tsukui, Christopher J. Molina, Vincent C. Auyeung, Dean Sheppard, Baosheng Li, Mazharul Maishan, Hiroki Taenaka, Michael A. Matthay, Rieko Muramatsu, Lenka Maliskova, Arnab Ghosh, Walter L. Eckalbar, Ari B. Molofsky, Stanley J. Tamaki, Trever G. Bivona, Adam R. Abate, Allon Wagner, Satish K. Pillai, Paul J. Wolters, Kevin M. Tharp, Mallar Bhattacharya
Alveolar macrophages are implicated in the development of lung fibrosis in mice after the administration of bleomycin (1). Their role in patients with interstitial lung disease (ILD), however, has been controversial; although clinical trials of nonselective antiinflammatory therapies, most importantly corticosteroids, have failed to show benefit in patients with idiopathic pulmonary fibrosis (IPF) (2), clinical trials of antiinflammatory therapies have shown benefit in patients with connective tissue disease–associated ILD (3).
In both normal and fibrotic human lungs, the receptor for colony stimulating factor 1 (CSF1R) is exclusively expressed by alveolar and interstitial macrophages and dendritic cells. Recently, Wolff et al. published the results of a phase II clinical trial of axatilimab, an inhibitory antibody targeting the CSF1R, in patients with multiorgan fibrosis secondary to graft-versus-host disease (GVHD) refractory to other therapies (4). The results of the trial were impressive, with an overall response rate of 74%. Remarkably, 26% of patients showed reversal of established fibrosis in the skin and 47% showed improvement in lung fibrosis as measured by symptoms or pulmonary function tests. These data led to rapid FDA approval of axatilimab for treatment of refractory GVHD and initiation of the MAXPIRe trial of axatilimab in patients with IPF (ClinicalTrials.gov NCT06132256). If confirmed in larger trials, axatilimab would be the only example of a therapy that reverses established lung fibrosis in humans. These findings create an urgent need to understand the mechanistic link between CSF1R-expressing cells and the disordered epithelial repair and fibroblast activation implicated in lung fibrosis.
In this issue of the JCI, Yadav et al. describe one such mechanism (5). They build upon work in mice suggesting that inhibiting CSF1R interrupts reciprocal signaling loops between alveolar macrophages and fibroblasts to reverse established fibrosis induced by asbestos administration (6). Yadav and colleagues found that monocyte-derived alveolar macrophages expressed arginase 1 (ARG1), the enzyme responsible for production of ornithine, which augments proline and collagen synthesis by fibroblasts. Fibroblasts in turn produced IL-6 to promote ARG1 expression in CSFR1+ alveolar macrophages in response to signaling by extracellular ATP, thus underscoring the reciprocal interactions between these macrophages and fibroblasts in fibrotic disease. Using a rigorous experimental design, Yadav et al. used high-depth spatial transcriptomics to show that human ARG1 was not detected in monocyte-derived alveolar macrophages. Instead, ARG1 was readily and robustly detected in human neutrophils, reflecting an important discrepancy between humans and mouse models.
The results reported by Yadav et al. (5) are important in themselves and raise critical questions for the field. First, which populations of CSF1R-expressing cells in the fibrotic lung directly mediate fibrosis? Second, do these cells cause fibrosis through direct interactions with fibroblasts in the interstitium? Third, what are the limitations of murine models of lung fibrosis, and can inflammatory cells be successfully incorporated into existing human platforms (e.g., precision cut lung slices and organoids) to better model human lung fibrosis? Given the possibility of reversing established lung fibrosis in some patients, excitement around these questions is high.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)