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, 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.