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PMID: 19398754 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Myeloid heme oxygenase-1 regulates innate immunity and autoimmunity by modulating IFN-beta production.

The Journal of experimental medicine ·Vol. 206 ·No. 5 ·2009-05-11 ·Pages 1167-79

Tzima S, Victoratos P, Kranidioti K, Alexiou M, Kollias G

Abstract

Heme oxygenase-1 (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-1(M-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-deficient macrophages show reduced expression of IFN-beta 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-beta 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-beta, 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-beta production, establishing HO-1 as a critical early mediator of the innate immune response.

MeSH Terms
Animals Autoimmunity/genetics Crosses, Genetic Heme Oxygenase-1/deficiency,genetics,immunology Homeostasis/immunology Immunity, Innate/genetics Integrases/genetics Interferon-beta/biosynthesis,genetics,immunology Listeria monocytogenes Listeriosis/immunology,mortality Mice Mice, Knockout Mice, Transgenic Myeloid Cells/enzymology Survivors Toll-Like Receptor 3/immunology Toll-Like Receptor 4/immunology
Chemicals
TLR3 protein, mouse Tlr4 protein, mouse Toll-Like Receptor 3 Toll-Like Receptor 4 Interferon-beta Heme Oxygenase-1 Cre recombinase Integrases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Tzima Sotiria
Biomedical Sciences Research Center Alexander Fleming, Vari 166-72, Greece.
Victoratos Panayiotis
Kranidioti Ksanthi
Alexiou Maria
Kollias George
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20081582
Published
2009-05-11
Epub
2009-00-27
Pages
1167-79
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2715044
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20081582 PMC Full Text View journal details
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