Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells

Blasius, Amanda L.; Arnold, Carrie; Georgel, Philippe; Rutschmann, Sophie; Xia, Yu; Lin, Pei; Ross, Charles; Li, Xiaohong; Smart, Nora G.; Beutler, Bruce

doi:10.1073/pnas.1014051107

Cited by 177 publications

(234 citation statements)

References 45 publications

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“…To directly examine how pDCs contribute to systemic autoimmunity, we developed congenic C57BL/6-Fas lpr mice carrying the feeble mutation of Slc15a4. In normal background mice with this mutation, development of both pDCs and cDCs is intact, but cytokine production, particularly type I IFNs, in response to TLR7 or TLR9 ligands is absent only in pDCs (27). Accordingly, in Slc15a4 mutant C57BL/6-Fas lpr mice, pDCs were present at normal frequencies in spleen (Fig.…”

Section: Feeble Mutation Of Slc15a4 Prevents Autoimmunity In Congenicmentioning

confidence: 89%

“…However, IRF8 deficiency prevents us from stating a definite conclusion as to whether pDCs contribute to disease solely through hyperproduction of type I IFNs or other functions, such as antigen presentation (57). The recent identification of the mutant strain feeble, in which defective expression of the peptide/histidine transporter SLC15A4 leads to absence of endosomal TLR signaling and severely reduced production of proinflammatory cytokines, including type I IFNs, specifically in pDCs (27), has provided an experimental tool to address this question. We found that lupus-predisposed C57BL/6-Fas lpr mice carrying this mutation exhibited striking reductions in disease manifestations and extended survival, despite efficient B-cell responses to both endosomal TLR stimuli and conventional exogenous antigens.…”

Section: Discussionmentioning

confidence: 99%

“…These cells, known as plasmacytoid DCs (pDCs), are the most potent producers of type I IFNs, a functional characteristic attributed to constitutive expression of TLR7, TLR9, and IRF7 and likely signaling from a unique intracellular compartment (24)(25)(26)(27). The involvement of pDCs in lupus is further suggested by the reduced frequency of these cells in patient blood together with increases in afflicted organs, presumably caused by the attraction of activated pDCs to inflammatory sites (10).…”

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confidence: 99%

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Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Baccalà¹,

Gonzalez-Quintial²,

Blasius

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effects were observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and -independent antigens. Moreover, Slc15a4 mutant C57BL/6-Fas lpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.E xtensive evidence suggests that type I IFNs are major pathogenic effectors in lupus-associated systemic autoimmunity. A well-documented pattern of expression of type I IFN-inducible genes occurs in peripheral blood mononuclear cells of patients with systemic lupus erythematosus (SLE) (1-3), and reduced disease is observed in some lupus-predisposed mice that either lack the common receptor (IFNAR) for these cytokines (4, 5) or have been treated with IFNAR-blocking antibody (6). Consequently, attention has focused on defining the cell subsets and signaling processes involved in type I IFN production, the mechanisms by which these mediators accelerate disease, and approaches to interfere with these pathogenic events.Early in vitro studies showed that type I IFN production can be induced in normal blood leukocytes by SLE autoantibodies complexed with nucleic acid-containing apoptotic/necrotic cell material, and further work demonstrated that this activity is sensitive to RNase and DNase digestion (7,8). These results were integrated in a more comprehensive scheme following the demonstration that type I IFN induction by these complexes is mediated by the engagement of endosomal Toll-like receptors (TLRs) (9-11). Similarly, antigenic cargo containing nucleic acids was found to promote B-cell proliferation in a TLR9-or TLR7-dependent manner, with this effect enhanced by type I IFN signaling (9, 12, 13). The contribution of nucleic acid-sensing TLRs to systemic autoimmunity was further corroborated by studies in lupus-predisposed mice lacking or overexpressing TLR7 and/or TLR9 (14-20), and in Unc93b1 (3d) mutant mice i...

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Section: Feeble Mutation Of Slc15a4 Prevents Autoimmunity In Congenicmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Baccalà¹,

Gonzalez-Quintial²,

Blasius

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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121

120

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“…A unique membrane trafficking pathway with characteristics of endolysosomes are essential for TLR7/9 signaling and IFN production in pDCs (22,32,33). The nucleic acid-containing amyloid is retained in the early endosomes of pDCs, where the prolonged TLR9 activation can promote MyD88 signaling and subsequent IRF7 activation, which initiates the transcription of all IFN-I subtypes.…”

Section: Discussionmentioning

confidence: 99%

Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity

Domizio¹,

Dorta‐Estremera²,

Gagea

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms that are not fully understood. In systemic lupus erythematosus, type I IFN (IFN-I) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Previously, we found that amyloid precursor proteins form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFNα/β production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of selfantigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid-containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.autoimmune disease | innate immune response | disease model

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“…However, TLR7 trafficking from the endolysosomes to the cell surface likely results from lysosomal exocytosis. Lysosomes specialized for secretion are known as lysosome-related organelles (LROs), where TLR7 and TLR9 are localized and deliver a signal 25,26 . AP-3 and the HermanskyPudlak syndrome proteins BLOC-1 and BLOC-2 have been shown to play a role in LRO biogenesis and TLR7/9 responses 25,26 .…”

Section: Discussionmentioning

confidence: 99%

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

et al. 2015

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Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that TLR7 is present on the cell surface of immune cells and that TLR7 responses can be inhibited by an anti-TLR7 antibody. The anti-TLR7 antibody is internalized with TLR7 and accumulates in endolysosomes as an immune complex. TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-TLR7 antibody. Furthermore, the anti-TLR7 antibody inhibits in vivo cytokine production induced by a TLR7 ligand. Spontaneous TLR7 activation in Unc93b1 D34A/D34A mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-TLR7 antibody treatment. These results demonstrate that cell surface TLR7 is a promising target for therapeutic intervention in autoimmune diseases.

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Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells

Cited by 177 publications

References 45 publications

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

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