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Here, we leveraged a highly compartmentalized model of skin inflammation and identified a surprising type I interferon (IFN)-mediated activation of hematopoietic stem\/progenitor cells (HSPCs) that results in profound changes to systemic host responses. Post-inflamed mice were protected from atherosclerosis and had worse outcomes following influenza virus infection. This IFN-mediated HSPC modulation was dependent on IFNAR signaling and could be recapitulated with the administration of recombinant IFN-\u03b1. Importantly, the transfer of post-inflamed HSPCs was sufficient to transmit the immune suppression phenotype. IFN modulation of HSPCs was rooted both in long-term changes in chromatin accessibility and the emergence of an IFN-responsive functional state from multiple progenitor populations. Collectively, our data reveal the profound and enduring effect of transient inflammation and more specifically type I IFN signaling and set the stage for a more nuanced understanding of HSPC functional modulation by peripheral immune signals.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf249","type":"journal-article","created":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:24:24Z","timestamp":1760289864000},"source":"Crossref","is-referenced-by-count":3,"title":["Interferon-sensitized hematopoietic progenitors dynamically alter organismal immunity"],"prefix":"10.1093","volume":"215","author":[{"given":"Maria","family":"Guillamot","sequence":"first","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine , New York, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenceslao","family":"Martinez-Navarrete","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Genetic Medicine, University of Chicago Pritzker School of Medicine , Chicago, IL,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Major","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immunotherapy, Department of Dermatology, Icahn School of Medicine at Mt Sinai , New York, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ipsita","family":"Subudhi","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine , New York, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varvara","family":"Paraskevopoulou","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine , New York, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandr","family":"Prystupa","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine , New York, NY,","place":["United States"]},{"name":"Department of Immunology and Immunotherapy, Department of Dermatology, Icahn School of Medicine at Mt Sinai , New York, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikjot","family":"Sidhu","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine , New York, NY,","place":["United States"]},{"name":"Department of Immunology and Immunotherapy, Department of Dermatology, Icahn School of Medicine at Mt Sinai , New York, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Yeaton","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine , New York, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filadelfia","family":"Tadjibaeva","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immunotherapy, Department of Dermatology, Icahn School of Medicine at Mt Sinai , New York, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Laskou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Leon H. 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