{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:19:06Z","timestamp":1788877146400,"version":"build-2803163510"},"reference-count":48,"publisher":"American Society for Clinical Investigation","issue":"9","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"vor","delay-in-days":51,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,1]]},"abstract":"<jats:p>\n                    Phosphorylation of Smad3 is a critical mediator of TGF-\u03b2 signaling, which plays an important role in regulating innate immune responses. However, whether Smad3 activation can be regulated in innate immune cells in TGF-\u03b2\u2013independent 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-\u03b2\u2013independent 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 (\n                    <jats:italic>\n                      Acvr1b\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      -\n                    <\/jats:italic>\n                    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\u2013dependent manner.\n                  <\/jats:p>","DOI":"10.1172\/jci187063","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T12:01:01Z","timestamp":1741694461000},"source":"Crossref","is-referenced-by-count":10,"title":["Activin A activation of Smad3 mitigates innate inflammation in mouse models of psoriasis and sepsis"],"prefix":"10.1172","volume":"135","author":[{"given":"Thierry","family":"Gauthier","sequence":"first","affiliation":[{"name":"Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, 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