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: 12.52). 01/2009; 205(13):2995-3006. DOI: 10.1084/jem.20080462
Source: PubMed


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.

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    • "Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by a complex interplay between innate and adaptive immune systems. Nucleic acid sensing receptors such as TLR7 and TLR9, which recognise RNA and DNA, respectively, have been shown to contribute to autoantibody and type I interferon (IFN) production in SLE [1]–[4]. In this context the transcription factor IRF5, which promotes pro-inflammatory cytokines and type I IFN production in response to both TLR7 and -9 activation, has been genetically and functionally associated with SLE [5]–[7]. "
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    ABSTRACT: IRF5 is a member of the Interferon Regulatory Factor (IRF) family of transcription factors activated downstream of the Toll-Like receptors (TLRs). Polymorphisms in IRF5 have been shown to be associated with the autoimmune disease Systemic Lupus Erythematosus (SLE) and other autoimmune conditions, suggesting a central role for IRF5 in the regulation of the immune response. Four different IRF5 isoforms originate due to alternative splicing and to the presence or absence of a 30 nucleotide insertion in IRF5 exon 6. Since the polymorphic region disturbs a PEST domain, a region associated with protein degradation, we hypothesized that the isoforms bearing the insertion might have increased stability, thus explaining the association of individual IRF5 isoforms with SLE. As the E3 ubiquitin ligase TRIpartite Motif 21 (TRIM21) has been shown to regulate the stability and hence activity of members of the IRF family, we investigated whether IRF5 is subjected to regulation by TRIM21 and whether dysregulation of this mechanism could explain the association of IRF5 with SLE. Our results show that IRF5 is degraded following TLR7 activation and that TRIM21 is involved in this process. Comparison of the individual IRF5 variants demonstrates that isoforms generated by alternative splicing are resistant to TRIM21-mediated degradation following TLR7 stimulation, thus providing a functional link between isoforms expression and stability/activity which contributes to explain the association of IRF5 with SLE.
    PLoS ONE 08/2014; 9(8):e103609. DOI:10.1371/journal.pone.0103609 · 3.23 Impact Factor
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    • "The role played by innate immune activation in initiating the autoreactive humoral response has not been extensively studied. Hydrocarbon oil pristine triggers profound inflammation and IFN production; the latter is essential to the development of autoantibodies and glomerulonephritis in non-autoimmune mice [139,140]. This finding thus highlights an equally critical role of type I IFN in the induced and spontaneous systemic autoimmunity. "
    Wei Cao ·
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) were initially identified as the prominent natural type I interferon-producing cells during viral infection. Over the past decade, the aberrant production of interferon α/β by pDCs in response to self-derived molecular entities has been critically implicated in the pathogenesis of systemic lupus erythematosus and recognized as a general feature underlying other autoimmune diseases. On top of imperative studies on human pDCs, the functional involvement and mechanism by which the pDC-interferon α/β pathway facilitates the progression of autoimmunity have been unraveled recently from investigations with several experimental lupus models. This article reviews correlating information obtained from human in vitro characterization and murine in vivo studies and highlights the fundamental and multifaceted contribution of pDCs to the pathogenesis of systemic autoimmune manifestation.
    04/2014; 5(2):212. DOI:10.4172/2155-9899.1000212
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    • "The most severe aspects of disease are dependent on type I IFN; type I IFN receptor-deficient (Ifnar−/−) mice exposed to pristane exhibit markedly reduced lupus-specific autoantibodies, proteinuria and glomerular hypercellularity [92]. Type I IFN expression, autoantibody production and glomerulonephritis in pristane-treated mice are primarily mediated via a TLR7- and MyD88-dependent pathway [93,94]. In addition, deficiencies in TLR4 and TLR9 also impact disease severity [95]. "
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    ABSTRACT: There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Although the specific environmental agents and how they promote autoimmunity remain largely unknown, in part because of diverse etiologies, environmentally induced autoimmune models can provide insights into potential mechanisms. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. By contrast, although the innate immune system is indispensable for autoimmunity, there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases, suggesting distinct autoimmune-promoting pathways. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Accordingly, idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity, although dependent on nucleic acid-binding toll-like receptors, does not require type I interferon but needs proinflammatory cytokines. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity.
    BMC Medicine 04/2013; 11(1):100. DOI:10.1186/1741-7015-11-100 · 7.25 Impact Factor
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