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ResearchIn-Press PreviewImmunologyPulmonology Open Access | 10.1172/JCI188734

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

Preeti Yadav,1 Javier Gómez Ortega,1 Prerna Dabral,2 Whitney Tamaki,3 Charles Chien,4 Kai-Chun Chang,5 Nivedita Biswas,1 Sixuan Pan,6 Julia Nilsson,7 Xiaoyang Yin,8 Aritra Bhattacharyya,1 Kaveh Boostanpour,1 Tanay Jujaray,1 Jasper T. Wang,1 Tatsuya Tsukui,1 Christopher J. Molina,1 Vincent C. Auyeung,1 Dean Sheppard,1 Baosheng Li,8 Mazharul Maishan,1 Hiroki Taenaka,1 Michael A. Matthay,1 Rieko Muramatsu,9 Lenka Maliskova,10 Arnab Ghosh,10 Walter L. Eckalbar,10 Ari B. Molofsky,7 Stanley J. Tamaki,10 Trever G. Bivona,3 Adam R. Abate,6 Allon Wagner,4 Satish K. Pillai,2 Paul J. Wolters,1 Kevin M. Tharp,11 and Mallar Bhattacharya1

1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

Find articles by Tamaki, W. in: PubMed | Google Scholar |

1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Med, UCSF, San Francisco, United States of America

2Vitalant Research Institute, San Francisco, United States of America

3Department of Medicine, UCSF, San Francisco, United States of America

4Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

5Twist Bioscience, San Francisco, United States of America

6Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, United States of America

7Department of Laboratory Medicine, UCSF, San Francisco, United States of America

8Department of Radiation Oncology, Shandong Academy of Medical Sciences, Jinan, China

9Department of Molecular Pharmacology, National Institute of Neuroscience, National Institute of Neurology and Psychiatry, Kodaira, Japan

10UCSF CoLabs, UCSF, San Francisco, United States of America

11Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Cente, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

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Published August 28, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI188734.
Copyright © 2025, Yadav et al. 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/.
Published August 28, 2025 - Version history
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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 to be 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 find that this pathway is regulated by cell-to-cell crosstalk, starting with purinergic signaling: Extracellular ATP (eATP) 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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