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The IFN-Inducible GTPase LRG47 (Irgm1) Negatively Regulates TLR4-Triggered Proinflammatory Cytokine Production and Prevents Endotoxemia¹

Andre Bafica^2,*,, Carl G. Feng^*, Helton C. Santiago, Julio Aliberti, Allen Cheever^*, Karen E. Thomas^¶, Gregory A. Taylor^||,#, Stefanie N. Vogel^¶ and Alan Sher^*

^* Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Division of Immunology, Department of Microbiology and Parasitology, Federal University of Santa Catarina, Florianopolis, SC, Brazil; Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; ^¶ Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201; ^|| Geriatric Research, Education, and Clinical Center, VA Medical Center, and ^# Department of Medicine, Immunology, and Department of Molecular Genetics and Microbiology, and Center for the Study of Aging, Duke University, Durham, NC 27710

LRG47/Irgm1, a 47-kDa IFN-inducible GTPase, plays a major role in regulating host resistance as well as the hemopoietic response to intracellular pathogens. LRG47 expression in macrophages has been shown previously to be stimulated in vitro by bacterial LPS, a TLR4 ligand. In this study, we demonstrate that induction of LRG47 by LPS is not dependent on MyD88 signaling, but rather, requires STAT-1 and IFN-. In addition, LRG47-deficient mice are highly susceptible to LPS, but not TLR2 ligand-induced shock, an outcome that correlates with enhanced proinflammatory cytokine production in vitro and in vivo. Further analysis revealed that LPS-stimulated LRG47-deficient macrophages display enhanced phosphorylation of p38, a downstream response associated with TLR4/MyD88 rather than IFN-/STAT-1 signaling. In contrast, LPS-induced phosphorylation of IFN regulatory factor-3 and expression of IFN- or the type I IFN-regulated genes, CCL5 and CCL10, were unaltered in LRG47^–/– cells. Together, these observations indicate that in LPS-stimulated murine macrophages LRG47 is induced by IFN- and negatively regulates TLR4 signaling to prevent excess proinflammatory cytokine production and shock. Thus, our findings reveal a new host-protective function for this GTPase in the response to pathogenic encounter.

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 This work was supported in part by the intramural research program of the National Institute of Allergy and Infectious Diseases. This grant was supported in part by National Institutes of Health Grant AI-18797 (to S.N.V.).

² Address correspondence and reprint requests to Dr. Andre Bafica, Immunobiology Section, Laboratory of Parasitic Diseases-National Institute of Allergy and Infectious Diseases-National Institutes of Health, 50 NIH South Drive, Room 6146, Bethesda, MD 20892. E-mail address: abafica{at}niaid.nih.gov

³ Abbreviations used in this paper: BM, bone marrow; ATF-2, activating transcription factor-2; BMM, BM-derived macrophage; IRAK, IL-1R-associated kinase; IRF, IFN regulatory factor; Pam₃Cys, S-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser-Lys4-OH, trihydrochloride; TIR, Toll/IL1 receptor; TRIF, TIR domain-containing adapter protein-inducing IFN-; WT, wild type.

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