TLR7-dependent and FcγR-independent production of type I interferon in experimental mouse lupus

Division of Rheumatology and Clinical Immunology and Center for Autoimmune Disease, University of Florida, Gainesville, FL 32610, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 01/2009; 205(13):2995-3006. DOI: 10.1084/jem.20080462
Source: PubMed

ABSTRACT Increased type I interferon (IFN-I) production and IFN-stimulated gene (ISG) expression are linked to the pathogenesis of systemic lupus erythematosus (SLE). Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibody-mediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D.C., K.M. Kelly-Scumpia, P.Y. Lee, J.S. Weinstein, R. Lyons, E. Sobel, M. Satoh, and W.H. Reeves. 2007. Arthritis Rheum. 56:3770-3783). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Toll-like receptor (TLR) 7- and myeloid differentiation factor 88 (MyD88)-dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplified by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fcgamma receptors (FcgammaRs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by FcgammaRs.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammatory conditions, such as in autoimmune disease, can disturb immune cell homeostasis and induce the expansion of normally rare cell populations. In our analysis of various murine models of lupus, we detect increased frequency of an uncommon subset identified as NK1.1+CD11c+CD122+MHC class II+. These cells share characteristics with the NK cell lineage and with cells previously described as IFN-producing killer dendritic cells: 1) they depend on IL-15 and express E4BP4; 2) they are cytotoxic and produce type I and type II IFN upon activation; and 3) they are efficient APCs both through MHC class II expression and in cross-presentation to CD8s. These atypical NK cells are responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They are highly proliferative as assessed by in vivo BrdU incorporation. In adoptive transfer experiments they persist in high numbers for months and maintain their surface marker profile, indicating that this population is developmentally stable. Gene expression analyses on both mRNA and microRNAs show a modified cell cycle program in which various miR-15/16 family members are upregulated, presumably as a consequence of the proliferative signal mediated by the increased level of growth factors, Ras and E2F activity. Alternatively, low expression of miR-150, miR-181, and miR-744 in these cells implies a reduction in their differentiation capacity. These results suggest that cells of the NK lineage that undergo TLR stimulation might turn on a proliferative program in detriment of their full differentiation into mature NK cells.
    The Journal of Immunology 01/2015; DOI:10.4049/jimmunol.1402673 · 5.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The risk of developing systemic lupus erythematosus (SLE) is about 9 times higher among women compared to men. However, very little is understood about the underlying mechanisms that contribute to this gender bias. Further, whether there is a link between immune response initiated in the gut mucosa, the progression of SLE, and the associated gender bias, has never been investigated. In this report, we show a potential link between immune response of the gut mucosa and SLE, and gender bias of lupus for the first time. Both plasma cell and gut imprinted- 4β7 T cell frequencies were significantly higher in the spleen and gut mucosa of female (SWRxNZB)F1 (SNF1) mice compared to that of their male counterparts. Importantly, female SNF1 mice not only showed profoundly higher CD45+ immune cell densities, but also carried large numbers of IL-17, IL-22 and IL-9 producing cells in the lamina propria (LP) compared to their male counterparts. Intestinal mucosa of female SNF1 mice expressed higher level of a large array of pro-inflammatory molecules including type 1 interferons and toll-like receptors 7 and 8 (TLR7 and TLR8), even before puberty. Our work, therefore, indicates that gut immune system may play a role in the initiation and progression of disease in SLE and the associated gender bias. This article is protected by copyright. All rights reserved. © 2015 British Society for Immunology.
    Clinical & Experimental Immunology 01/2015; DOI:10.1111/cei.12587 · 3.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to express negative regulators of immune activation and thus were hyperresponsive to TLR ligands, producing abnormally high levels of proinflammatory cytokines. This hyperreactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes in vivo. Collectively these findings reveal an unexpected negative regulatory role for STING, having important implications for STING-directed therapies.
    Proceedings of the National Academy of Sciences 02/2015; DOI:10.1073/pnas.1420217112 · 9.81 Impact Factor

Full-text (5 Sources)

Available from
May 29, 2014