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Murine Dendritic Cell Type I IFN Production Induced by Human IgG-RNA Immune Complexes Is IFN Regulatory Factor (IRF)5 and IRF7 Dependent and Is Required for IL-6 Production¹

Kei Yasuda^*, Christophe Richez^*, Joseph W. Maciaszek^*, Neerja Agrawal^*, Shizuo Akira, Ann Marshak-Rothstein and Ian R. Rifkin^2,*

^* Renal Section, Department of Medicine and Department of Microbiology, Boston University School of Medicine, Boston, MA 02118; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Osaka, Japan

Dendritic cell (DC) activation by nucleic acid-containing IgG complexes is implicated in systemic lupus erythematosus (SLE) pathogenesis. However, it has been difficult to definitively examine the receptors and signaling pathways by which this activation is mediated. Because mouse FcRs recognize human IgG, we hypothesized that IgG from lupus patients might stimulate mouse DCs, thereby facilitating this analysis. In this study, we show that sera and purified IgG from lupus patients activate mouse DCs to produce IFN-, IFN-, and IL-6 and up-regulate costimulatory molecules in a FcR-dependent manner. This activation is only seen in sera with reactivity against ribonucleoproteins and is completely dependent on TLR7 and the presence of RNA. As anticipated, IFN regulatory factor (IRF)7 is required for IFN- and IFN- production. Unexpectedly, however, IRF5 plays a critical role in IFN- and IFN- production induced not only by RNA-containing immune complexes but also by conventional TLR7 and TLR9 ligands. Moreover, DC production of IL-6 induced by these stimuli is dependent on a functional type I IFNR, indicating the need for a type I IFN-dependent feedback loop in the production of inflammatory cytokines. This system may also prove useful for the study of receptors and signaling pathways used by immune complexes in other human diseases.

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 by grants from the National Institutes of Health and the Lupus Research Institute (to I.R.R.). C.R. was supported by grants from Société Française de Rhumatologie, Centre Hospitalier Universitaire de Bordeaux, and Réseau Rhumatologie.

² Address correspondence and reprint requests to Dr. Ian R. Rifkin, Renal Section, Department of Medicine, Boston University School of Medicine, EBRC 5th Floor, 650 Albany Street, Boston, MA 02118. E-mail address: irifkin{at}bu.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic cell; cDC, conventional DC; FL, fms-like tyrosine kinase 3 ligand; FL-DC, DC obtained from bone marrow cells cultured in FL; IRF, IFN regulatory factor; pDC, plasmacytoid DC; poly(I:C), poly(deoxyinosinic-deoxycytidylic acid); RNP, ribonucleoprotein; Sm, Smith Ag; WT, wild type.

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