The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20081582
The Journal of Experimental Medicine, Vol. 206, No. 5, 1167-1179
The Rockefeller University Press, 0022-1007 $30.00
© Tzima et al.
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ARTICLE

 Myeloid heme oxygenase–1 regulates innate immunity and autoimmunity by modulating IFN-β production

Sotiria Tzima, Panayiotis Victoratos, Ksanthi Kranidioti, Maria Alexiou, and George Kollias

Biomedical Sciences Research Center "Alexander Fleming," Vari 166-72, Greece

CORRESPONDENCE George Kollias: kollias{at}fleming.gr

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-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–deficient macrophages show reduced expression of IFN-β 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-β 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-β, 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-β production, establishing HO-1 as a critical early mediator of the innate immune response.

Abbreviations used: AP-1, adaptor protein 1; BMDM, BM macrophage; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; GST, glutathione S-transferase; HO-1, heme oxygenase–1; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; LFB, luxol fast blue; MAPK, mitogen-activated protein kinase; MDA5, melanoma differentiation–associated gene 5; MOG, myelin oligodendrocyte glycoprotein; MOI, multiplicity of infection; PKR, protein kinase regulated by RNA; RIG-I, retinoic acid–inducible gene I; SeV, Sendai virus; TEPM, thioglycollate-elicited peritoneal macrophage; TIR, TLR–IL-1R; TLR, Toll-like receptor; TRIF, TIR domain–containing adaptor inducing IFN-β; WCE, whole-cell extract.

© 2009 Tzima et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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