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 production.
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 FcgammaRs 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-alpha, IFN-beta, and IL-6 and up-regulate costimulatory molecules in a FcgammaR-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-alpha and IFN-beta production. Unexpectedly, however, IRF5 plays a critical role in IFN-alpha and IFN-beta 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.
Yasuda
Kei
K
Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Richez
Christophe
C
Maciaszek
Joseph W
JW
Agrawal
Neerja
N
Akira
Shizuo
S
Marshak-Rothstein
Ann
A
Rifkin
Ian R
IR
D000818:Animals; D000936:Antigen-Antibody Complex / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007370:Interferon Type I / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000378:metabolism / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000378:metabolism / Q000502:physiology
D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D015850:Interleukin-6; C498178:Irf5 protein, mouse; D008024:Ligands; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D012313:RNA