{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T19:26:31Z","timestamp":1793820391625,"version":"4.6.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32000638, 82071778"],"award-info":[{"award-number":["32000638, 82071778"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Initial lipopolysaccharide (LPS) exposure leads to a hypo-responsive state by macrophages to a secondary stimulation of LPS, known as endotoxin tolerance. However, recent findings show that functions of endotoxin-tolerant macrophages are not completely suppressed, whereas they undergo a functional re-programming process with upregulation of a panel of molecules leading to enhanced protective functions including antimicrobial and tissue-remodeling activities. However, the underlying molecular mechanisms are still elusive. Erythropoietin (EPO), a glycoprotein regulated by hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1), exerts anti-inflammatory and tissue-protective activities. Nevertheless, the potential effects of EPO on functional re-programming of endotoxin-tolerant macrophages have not been investigated yet. Here, we found that initial LPS exposure led to upregulation of HIF-1\u03b1\/EPO in macrophages and that EPO enhanced tolerance in tolerized macrophages and mice as demonstrated by suppressed proinflammatory genes such as\n                    <jats:italic>Il1b<\/jats:italic>\n                    ,\n                    <jats:italic>Il6<\/jats:italic>\n                    , and\n                    <jats:italic>Tnfa<\/jats:italic>\n                    after secondary LPS stimulation. Moreover, we showed that EPO improved host protective genes in endotoxin-tolerant macrophages and mice, such as the anti-bacterial genes coding for cathelicidin-related antimicrobial peptide (\n                    <jats:italic>Cnlp<\/jats:italic>\n                    ) and macrophage receptor with collagenous structure (\n                    <jats:italic>Marco<\/jats:italic>\n                    ), and the tissue-repairing gene vascular endothelial growth factor C (\n                    <jats:italic>Vegfc<\/jats:italic>\n                    ). Therefore, our findings indicate that EPO mediates the functional re-programming of endotoxin-tolerant macrophages. Mechanistically, we found that PI3K\/AKT signaling contributed to EPO-mediated re-programming through upregulation of\n                    <jats:italic>Irak3<\/jats:italic>\n                    and\n                    <jats:italic>Wdr5<\/jats:italic>\n                    expression. Specifically, IL-1 receptor-associated kinase 3 (IRAK3) was responsible for inhibiting proinflammatory genes\n                    <jats:italic>Il1b<\/jats:italic>\n                    ,\n                    <jats:italic>Il6<\/jats:italic>\n                    , and\n                    <jats:italic>Tnfa<\/jats:italic>\n                    in tolerized macrophages after LPS rechallenge, whereas WDR5 contributed to the upregulation of host beneficial genes including\n                    <jats:italic>Cnlp<\/jats:italic>\n                    ,\n                    <jats:italic>Marco<\/jats:italic>\n                    , and\n                    <jats:italic>Vegfc<\/jats:italic>\n                    . In a septic model of mice, EPO pretreatment significantly promoted endotoxin-tolerant re-programming, alleviated lung injury, enhanced bacterial clearance, and decreased mortality in LPS-tolerized mice after secondary infection of\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    . Collectively, our results reveal a novel role for EPO in mediating functional re-programming of endotoxin-tolerant macrophages; thus, targeting EPO appears to be a new therapeutic option in sepsis and other inflammatory disorders.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.938944","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T04:13:56Z","timestamp":1660018436000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Erythropoietin mediates re-programming of endotoxin-tolerant macrophages through PI3K\/AKT signaling and protects mice against secondary 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