{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T18:03:44Z","timestamp":1793556224309,"version":"4.5.0"},"reference-count":32,"publisher":"American Society of Hematology","issue":"26","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,6,27]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Inflammatory responses must be tightly coordinated with the activation of emergency myelopoiesis to produce potent myeloid cells that fight infection without causing excessive host damage. Here, we show that granulocyte-macrophage colony-stimulating factor (GM-CSF) programs myeloid-committed progenitors to produce trained macrophages (increased cytokine response), but programs the upstream noncommitted LKS+ progenitors (defined as Lin\u2212 c-Kit+ Sca-1+ cells) to produce tolerized macrophages (decreased cytokine response). In myeloid progenitors, GM-CSF strongly activates signal transducer and activator of transcription 5 (STAT5), Ras-Raf-extracellular signal regulated kinase (ERK), and Akt-mTOR signaling pathways, which are essential to establish a training program, whereas in LKS+ progenitors, GM-CSF induces NF-\u03baB translocation to the nucleus to establish a tolerization program. These differences arise from higher GM-CSF receptor expression in myeloid progenitors compared with LKS+ cells. We demonstrate that \u03b2-catenin regulation of NF-\u03baB nuclear translocation is central in this process. In myeloid progenitors, glycogen synthase kinase 3 (GSK3) inactivation by strong ERK and phosphatidylinositol 3 kinase (PI3K)-Akt signaling increases cytoplasmic \u03b2-catenin levels to block NF-\u03baB nuclear translocation. In contrast, when ERK and PI3K-Akt signaling are weak, active GSK3 causes a decrease in \u03b2-catenin, allowing NF-\u03baB nuclear translocation in LKS+ progenitors. Finally, GM-CSF-induced LKS+ tolerization takes place in several murine models of trained immunity and in human CD34+ CD38\u2212 progenitors. Our study reveals that in addition to activating myelopoiesis, GM-CSF also programs early and immediate myeloid progenitors to produce opposing immune memory phenotypes. We propose that the inflammatory response from immediate myeloid progenitors may be balanced by the tolerized phenotype of early progenitors, thus providing a mechanism for appropriate resolution of inflammation and protection against a prolonged cytokine storm.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024024330","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T20:01:01Z","timestamp":1712865661000},"page":"2763-2777","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":19,"title":["GM-CSF receptor expression determines opposing innate memory phenotypes at different stages of myelopoiesis"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9063-5143","authenticated-orcid":false,"given":"Paula","family":"Guerrero","sequence":"first","affiliation":[{"name":"1Instituto de Biotecnolog\u00eda y Biomedicina, BIOTECMED, and Departamento de Microbiolog\u00eda y Ecolog\u00eda, Facultat de Ci\u00e8ncies Biol\u00f2giques, Universitat de Val\u00e8ncia, Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Bono","sequence":"additional","affiliation":[{"name":"1Instituto de Biotecnolog\u00eda y Biomedicina, BIOTECMED, and Departamento de Microbiolog\u00eda y Ecolog\u00eda, Facultat de Ci\u00e8ncies Biol\u00f2giques, Universitat de Val\u00e8ncia, Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Sob\u00e9n","sequence":"additional","affiliation":[{"name":"1Instituto de Biotecnolog\u00eda y Biomedicina, BIOTECMED, and Departamento de Microbiolog\u00eda y Ecolog\u00eda, Facultat de Ci\u00e8ncies Biol\u00f2giques, Universitat de Val\u00e8ncia, Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Guiu","sequence":"additional","affiliation":[{"name":"1Instituto de Biotecnolog\u00eda y Biomedicina, BIOTECMED, and Departamento de Microbiolog\u00eda y Ecolog\u00eda, Facultat de Ci\u00e8ncies Biol\u00f2giques, Universitat de Val\u00e8ncia, Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0161-1917","authenticated-orcid":false,"given":"Quen J.","family":"Cheng","sequence":"additional","affiliation":[{"name":"2Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0319-5678","authenticated-orcid":false,"given":"M. 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