ArticleThe Journal of clinical investigation2025
Activin A activation of Smad3 mitigates innate inflammation in mouse models of psoriasis and sepsis.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Combining bioinformatics and machine learning to analyze and validate sepsis-related cell senescence genes and potential drugs.Renal failure · 2026Article
- A portable nanobiosensor with machine learning: enabling multi-cytokines point-of-care testing and early identification of sepsis immunoparalysis.Journal of nanobiotechnology · 2026Article
- ActIIR inhibition improves motor outcome and preserves muscle fibers after experimental autoimmune neuritis.Acta neuropathologica communications · 2026Article
- Small noncoding RNA TY2 enhances efferocytosis and improves outcomes in a mouse model of sepsis.JCI insight · 2026Article
- RORγt-APCs: The New Masters of Oral Tolerance.Barrier immunity · 2025Article
- Activin A mitigates ferroptosis in cerebral ischemia/reperfusion injury via the PGC-1α/NRF1/TFAM axis.Frontiers in neurologyArticle
Corrections and comments
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Authors and funding
12 authors.
Funding
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.
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Registered trials
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