{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T13:13:18Z","timestamp":1789823598947,"version":"4.0.1"},"reference-count":50,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,5,11]]},"abstract":"<jats:p>Heme oxygenase\u20131 (HO-1) is a key cytoprotective, antioxidant, and antiinflammatory molecule. The pathophysiological functions of HO-1 have been associated with its enzymatic activities in heme catabolism. We have examined the immune functions of HO-1 by its conditional ablation in myeloid cells (HO-1M-KO mice). We demonstrate that myeloid HO-1 is required for the activation of interferon (IFN) regulatory factor (IRF) 3 after Toll-like receptor 3 or 4 stimulation, or viral infection. HO-1\u2013deficient macrophages show reduced expression of IFN-\u03b2 and of primary IRF3 target genes encoding RANTES, IP-10 and MCP-1. In the presence of polyI:C, myeloid HO-1 knockout mice infected with Listeria monocytogenes, a model dependent on IFN-\u03b2 production, showed enhanced bacterial clearance and survival, whereas control mice succumbed to infection. Moreover, after induction of experimental autoimmune encephalomyelitis, mice with myeloid-specific HO-1 deficiency developed a higher incidence and an exacerbated, nonremitting clinical disease correlating with persistent activation of antigen-presenting cells, enhanced infiltration of Th17 cells, and a nonregressing myelin-specific T cell reactivity. Notably, these defects were rectified by exogenous administration of IFN-\u03b2, confirming that HO-1 functions directly upstream of this critical immune pathway. These results uncover a novel direct function for myeloid HO-1 in the regulation of IFN-\u03b2 production, establishing HO-1 as a critical early mediator of the innate immune response.<\/jats:p>","DOI":"10.1084\/jem.20081582","type":"journal-article","created":{"date-parts":[[2009,4,27]],"date-time":"2009-04-27T22:04:39Z","timestamp":1240869879000},"page":"1167-1179","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":183,"title":["Myeloid heme oxygenase\u20131 regulates innate immunity and autoimmunity by modulating IFN-\u03b2 production"],"prefix":"10.1084","volume":"206","author":[{"given":"Sotiria","family":"Tzima","sequence":"first","affiliation":[{"name":"Biomedical Sciences Research Center \u201cAlexander Fleming,\u201d Vari 166-72, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panayiotis","family":"Victoratos","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Center \u201cAlexander Fleming,\u201d Vari 166-72, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ksanthi","family":"Kranidioti","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Center \u201cAlexander Fleming,\u201d Vari 166-72, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Alexiou","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Center \u201cAlexander Fleming,\u201d Vari 166-72, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Kollias","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Center \u201cAlexander Fleming,\u201d Vari 166-72, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2009,4,27]]},"reference":[{"key":"2023072917141757600_bib1","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/35099560","article-title":"Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3","volume":"413","author":"Alexopoulou","year":"2001","journal-title":"Nature."},{"key":"2023072917141757600_bib2","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1126\/science.282.5396.2085","article-title":"Defective LPS signaling in C3H\/HeJ and C57BL\/10ScCr mice: mutations in Tlr4 gene","volume":"282","author":"Poltorak","year":"1998","journal-title":"Science."},{"key":"2023072917141757600_bib3","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/ni758","article-title":"Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway","volume":"3","author":"Hemmi","year":"2002","journal-title":"Nat. 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Immunol."},{"key":"2023072917141757600_bib36","doi-asserted-by":"crossref","first-page":"7505","DOI":"10.4049\/jimmunol.177.11.7505","article-title":"Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta","volume":"177","author":"Touil","year":"2006","journal-title":"J. Immunol."},{"key":"2023072917141757600_bib37","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S1471-4906(03)00181-9","article-title":"Heme oxygenase-1: unleashing the protective properties of heme","volume":"24","author":"Otterbein","year":"2003","journal-title":"Trends Immunol."},{"key":"2023072917141757600_bib38","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1038\/3947","article-title":"Heme oxygenase: protective gene or Trojan horse","volume":"4","author":"Platt","year":"1998","journal-title":"Nat. Med."},{"key":"2023072917141757600_bib39","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/316552a0","article-title":"Identity of tumour necrosis factor and the macrophage-secreted factor cachectin","volume":"316","author":"Beutler","year":"1985","journal-title":"Nature."},{"key":"2023072917141757600_bib40","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1084\/jem.177.2.547","article-title":"Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia","volume":"177","author":"Gerard","year":"1993","journal-title":"J. Exp. Med."},{"key":"2023072917141757600_bib41","doi-asserted-by":"crossref","first-page":"8798","DOI":"10.1073\/pnas.161272598","article-title":"Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia","volume":"98","author":"Minamino","year":"2001","journal-title":"Proc. Natl. Acad. Sci. 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Sci."},{"key":"2023072917141757600_bib45","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/ni1254","article-title":"Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages","volume":"6","author":"Harrington","year":"2005","journal-title":"Nat. Immunol."},{"key":"2023072917141757600_bib46","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0165-5728(00)00384-2","article-title":"Modulation of the IL-10\/IL-12 cytokine circuit by interferon-beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis","volume":"111","author":"Tuohy","year":"2000","journal-title":"J. Neuroimmunol."},{"key":"2023072917141757600_bib47","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0165-5728(02)00098-X","article-title":"Interferon-beta directly influences monocyte infiltration into the central nervous system","volume":"127","author":"Floris","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"2023072917141757600_bib48","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1084\/jem.20040435","article-title":"Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases","volume":"200","author":"Xanthoulea","year":"2004","journal-title":"J. Exp. 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