Journal Article

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

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

2025

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Activin / Activins - genetics / Activins - immunology / Activins - metabolism / Animal models / Animals / Antibodies / CD73 antigen / Control / Development and progression / Disease Models, Animal / Health aspects / Humans / Imiquimod / Immune response / Immunity, Innate / Immunology / Inflammation / Inflammation - genetics / Inflammation - immunology / Inflammation - metabolism / Inflammation - pathology / Innate immunity / Kinases / Ligands / Macrophages / Macrophages - immunology / Macrophages - metabolism / Macrophages - pathology / Mice / Mice, Knockout / Phosphorylation / Physiological aspects / Proteins / Psoriasis / Psoriasis - chemically induced / Psoriasis - genetics / Psoriasis - immunology / Psoriasis - metabolism / Psoriasis - pathology / Sepsis / Sepsis - genetics / Sepsis - immunology / Sepsis - metabolism / Sepsis - pathology / Signal Transduction - immunology / Skin diseases / Smad proteins / Smad3 protein / Smad3 Protein - genetics / Smad3 Protein - immunology / Smad3 Protein - metabolism / Stat5 protein / Transcription factors / Transforming growth factor-b / Transforming growth factors