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ResearchIn-Press PreviewImmunologyInflammation Open Access | 10.1172/JCI187063

Activin A activation of Smad3 mitigates innate inflammation in mouse models of psoriasis and sepsis

Thierry Gauthier,1 Yun-Ji Lim,1 Wenwen Jin,1 Na Liu,1 Liliana C. Patiño,1 Weiwei Chen,1 James Warren,2 Daniel Martin,3 Robert J. Morell,3 Gabriela S. Dveksler,2 Gloria H. Su,4 and WanJun Chen1

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Gauthier, T. in: JCI | PubMed | Google Scholar

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Lim, Y. in: JCI | PubMed | Google Scholar |

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

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

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Liu, N. in: JCI | PubMed | Google Scholar

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Patiño, L. in: JCI | PubMed | Google Scholar

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

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

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Warren, J. in: JCI | PubMed | Google Scholar

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Martin, D. in: JCI | PubMed | Google Scholar

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Morell, R. in: JCI | PubMed | Google Scholar |

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Dveksler, G. in: JCI | PubMed | Google Scholar

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Su, G. in: JCI | PubMed | Google Scholar

1Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, United States of America

2Department of Pathology, Uniformed Services University, Bethesda, United States of America

3Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, United States of America

4Department of Pathology, Columbia University Irving Medical Center, New York, United States of America

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

Published March 11, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI187063.
Copyright © 2025, Gauthier 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 March 11, 2025 - Version history
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Abstract

Phosphorylation of Smad3 is a critical mediator of TGF-β signaling, which plays an important role in regulating innate immune responses. However, whether Smad3 activation can be regulated in innate immune cells in TGF-β-independent contexts remains poorly understood. Here, we show that Smad3 is activated through the phosphorylation of its C-terminal residues (pSmad3C) in murine and human macrophages in response to bacterial and viral ligands, which is mediated by Activin A in a TGF-β independent manner. Specifically, infectious ligands, such as LPS, induced secretion of Activin A through the transcription factor STAT5 in macrophages, and Activin A signaling in turn activated pSmad3C. This Activin A-Smad3 axis controlled the mitochondrial ATP production and ATP conversion into adenosine by CD73 in macrophages, enforcing an anti-inflammatory mechanism. Consequently, mice with a deletion of Activin A receptor 1b specifically in macrophages (Acvr1bf/f-Lyz2cre) succumbed more to sepsis due to uncontrolled inflammation and exhibited exacerbated skin disease in a mouse model of imiquimod-induced psoriasis. Thus, we have revealed a previously unrecognized natural brake to inflammation in macrophages that occurs through the activation of Smad3 in an Activin A-dependent manner.

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  • Version 1 (March 11, 2025): In-Press Preview
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