Activin A activation of Smad3 mitigates innate inflammation in mouse models of psoriasis and sepsis
Thierry Gauthier, … , Gloria H. Su, WanJun Chen
Thierry Gauthier, … , Gloria H. Su, WanJun Chen
Published March 11, 2025
Citation Information: J Clin Invest. 2025;135(9):e187063. https://doi.org/10.1172/JCI187063.
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Research Article Immunology Inflammation

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

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, and this activation 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 mitochondrial ATP production and ATP conversion into adenosine by CD73 in macrophages, enforcing an antiinflammatory mechanism. Consequently, mice with a deletion of activin A receptor 1b specifically in macrophages (Acvr1bfl/fl-Lyz2cre) succumbed more to sepsis as a result of 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.

Authors

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

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Figure 4

The activin A/Smad3 pathway supports ATP metabolism during inflammation.

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The activin A/Smad3 pathway supports ATP metabolism during inflammation....
(A) Heatmap representing significantly downregulated genes in macrophages from Smad3-KO mice (compared with WT macrophages) stimulated with LPS for 24 hours. (B and C) MitoTracker staining in macrophages stimulated with LPS for 24 hours and isolated from Smad3-KO mice (B) or Acvr1b-Lyz2cre mice (C). (D and E) ATP production (intracellular) in macrophages stimulated with LPS for 24 hours and isolated from Smad3-KO mice (D) (n = 6) or Acvr1b-Lyz2cre mice (E). (F and G) RT-qPCR analysis of Arg1 and Tgfbi expression in macrophages stimulated with LPS for 24 hours in combination (or not) with 20 μM of ATP and isolated from Smad3-KO mice (F) or Acvr1b-Lyz2cre mice (G). (H) RT-qPCR analysis of Nt5e (encoding CD73) expression in macrophages stimulated with LPS for 24 hours and isolated from Smad3-KO or Acvr1b-Lyz2cre mice. (I and J) RT-qPCR analysis of Tgfbi and Arg1 expression in macrophages stimulated with LPS for 24 hours in combination (or not) with ATP and a CD73 inhibitor or a CREB inhibitor and isolated from Smad3-KO mice (I) or Acvr1b-Lyz2cre mice (J). (F–J, n = 4.) Pooled or representative of at least 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001 by Student’s t test (B–G) or 1-way ANOVA (H–J).