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 3

LPS induces the activin A/Smad3 axis through a TLR4/MyD88/MAPK/STAT5 pathway.

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LPS induces the activin A/Smad3 axis through a TLR4/MyD88/MAPK/STAT5 pat...
(A) RT-qPCR analysis of Inhba expression in macrophages from WT or TLR4-KO mice stimulated 2 hours by LPS. (n = 6.) (B) RT-qPCR analysis of Inhba expression in macrophages from WT or MyD88-KO mice stimulated 2 hours by LPS. (n = 4.) (C) Protein abundance in macrophages stimulated 6 hours by LPS. (D) RT-qPCR analysis of Inhba expression in macrophages from WT or Traf6-Lyz2cre mice stimulated by LPS for 2 hours. (n = 6.) (E) Protein abundance in macrophages isolated stimulated 6 hours by LPS. (F) RT-qPCR analysis of Inhba expression in macrophages pretreated with a TAK1 inhibitor for 1 hour followed by LPS stimulation for 2 hours. (n = 6.) (G) Protein abundance in macrophages pretreated with a TAK1 inhibitor for 1 hour followed by LPS stimulation for 6 hours. (H) RT-qPCR analysis of Inhba expression in macrophages pretreated with MEK and ERK inhibitors for 1 hour followed by LPS stimulation for 2 hours. (n = 6.) (I) Protein abundance in macrophages pretreated 1 hour with MEK and ERK inhibitors followed by LPS stimulation for 6 hours. (J) Protein abundance in macrophages treated with LPS. (K) ChIP-coupled real-time PCR analysis of STAT5 enrichment in various sequences of the promoter region of the Inhba gene in macrophages treated with LPS for 2 hours. (n = 6.) (L) RT-qPCR analysis of Inhba expression in macrophages pretreated 1 hour with a STAT5 inhibitor followed by LPS stimulation for 2 hours. (n = 6.) (M) Protein abundance in macrophages pretreated 1 hour with a STAT5 inhibitor followed by LPS stimulation for 6 hours. (N) RT-qPCR analysis of Inhba expression in macrophages from WT or Stat5-Lyz2cre mice stimulated by LPS for 2 hours. (n = 6.) (O) Protein abundance in macrophages stimulated by LPS for 6 hours. Representative of at least 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001 by 1-way ANOVA.