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J. Biol. Chem., Vol. 283, Issue 5, 2724-2733, February 1, 2008

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Innate Immunity to Intraphagosomal Pathogens Is Mediated by Interferon Regulatory Factor 8 (IRF-8) That Stimulates the Expression of Macrophage-specific Nramp1 through Antagonizing Repression by c-Myc^*

Michal Alter-Koltunoff, Sigal Goren, Janna Nousbeck, Carl G. Feng, Alan Sher, Keiko Ozato^¶, Aviva Azriel, and Ben-Zion Levi, Incumbent of the Lily and Silvian Marcus Chair in Life Sciences at the Technion¹

From the Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel and the ^¶Laboratory of Molecular Growth Regulation, NICHD, and the Immunobiology Section, NIAID, National Institutes of Health Bethesda, Maryland 20892-8003

Macrophages are a central arm of innate immune defense against intracellular pathogens. They internalize microbes into phagosomes where the invaders are being killed by oxygen and nitrogen reactive species. Despite this battery of antimicrobial molecules, some are able to thrive within the phagosome thus termed intraphagosomal pathogens among which are Salmonella, Leishmania, and Mycobacteria. In mice, a single dominant gene termed Nramp1/Slc11a1 controls innate resistance to such pathogens. This gene is expressed exclusively in myeloid cells. Previously, we have shown that the restricted expression of Nramp1 is regulated by a myeloid cell-specific transcription factor termed IRF-8/ICSBP. It is demonstrated here that the induction of Nramp1 expression in activated macrophages is accompanied by a promoter shift from a repression state elicited by c-Myc to an activation state elicited by the induction of IRF-8 in activated macrophages. This transition from repression to activation is facilitated by a competitive protein-protein interaction with the transcription factor Miz-1. To show that IRF-8 is directly involved in the elimination of intraphagosomal pathogens through the regulation of Nramp1 gene expression, we bred wild type as well as IRF-8 and Nramp1 null mouse strains and examined macrophages derived from bone marrow and peritoneum. Our results clearly show that the absence of IRF-8 and Nramp1 leads to the same phenotype; defective killing of intraphagosomal Salmonella enterica serovar typhimurium and Mycobacterium bovis. Thus, interplay between repression and activation state of the Nramp1 promoter mediated by IRF-8 provides the molecular basis by which macrophages resist intraphagosomal pathogens at early stage after infection.

Received for publication, September 13, 2007 , and in revised form, October 19, 2007.

^* This work was supported in part by Israel Science Foundation Grant 536/01, the Center for the Study of Emerging Diseases, and the fund for the promotion of research at the Technion (to B. Z. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 972-4-8293345; Fax: 972-4-8293399; E-mail: blevi{at}technion.ac.il.

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