Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice

Santiago-Raber, Marie Laure; Dunand-Sauthier, Isabelle; Wu, Tianfu; Li, Quan Zhen; Uematsu, Satoshi; Akira, Shizuo; Reith, Walter; Mohan, Chandra; Kotzin, Brian L.; Izui, Shozo

doi:10.1016/j.jaut.2009.11.001

Cited by 187 publications

(183 citation statements)

References 58 publications

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“…3D), providing further evidence for a reduction of CNS inflammation in TLR7-deficient mice. Collectively, our results indicated that TLR7 plays an active and deleterious role in sustaining autoimmune responses in MOGinduced EAE, which is in line with previous observations in murine lupus [4,15,[27][28][29].…”

Section: Infiltration Of Inflammatory Cells In the Cns Of Tlr7 −/− MIsupporting

confidence: 92%

“…3D evidence for a reduction of CNS inflammation in TLR7-deficient mice. Collectively, our results indicated that TLR7 plays an active and deleterious role in sustaining autoimmune responses in MOGinduced EAE, which is in line with previous observations in murine lupus [4,15,[27][28][29].Inhibition of B-cell activation in TLR7 −/− mice is associated with decreased antibody responsesAs mentioned previously, self-derived nucleotides may reach B cell or pDC endosomes (containing TLR7) in autoimmune situations through the action of nucleotide-binding proteins such as autoantibodies [18]. Consequently, TLR7 is involved in the activation of B cells and pDCs by RNA-associated autoantigens through BCR and/or FcγR IC ligation and endocytosis followed by RNA autoantigen transfer from disrupted IC to TLR7.…”

supporting

confidence: 91%

“…The abundance of Tlr4, Tlr7 and Tlr9 mRNA was quantified by real-time PCR as described previously [29].…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

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TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

et al. 2013

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The innate Toll-like receptor 7 (TLR7) detects infections by recognizing viral and bacterial single-stranded RNA. In addition to pathogen-derived RNA, immune cells expressing high levels of TLR7, such as B cells and dendritic cells (DCs), can be activated by self-RNA. During myelin-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, TLR7 expression is increased within the central nervous system (CNS). To define the contribution of TLR7 to the development of EAE, we evaluated the course of the disease in C57BL/6-Tlr7-deficient mice compared with that in WT mice and found that TLR7-deficient mice had decreased disease severity. This protection was associated with decreased myelin oligodendrocyte glycoprotein-specific T-cell activation by primed DCs, decreased circulating autoantibodies, attenuated inflammation within the CNS, and increased Foxp3 + regulatory T cells in the periphery and in the CNS. In conclusion, we show that TLR7 is involved in the maintenance of autoimmunity in the pathogenesis of EAE.Keywords: EAE r IL-10 r Multiple sclerosis r TLR7 r Treg cell IntroductionRecognition of microbial components by Toll-like receptors (TLRs) is crucial for host responses against pathogens. While most TLRs are expressed on the cell surface, others such as TLR3, -7, -8, and -9 are expressed intracellularly within endosomal compartments where they detect nucleic acids. Endosomal TLRs recognize viral double-stranded RNA (TLR3), unmethylated CpG DNA Correspondence: Dr. Marie-Laure Santiago-Raber e-mail: marie.santiago@unige.ch (TLR9), and viral single-stranded RNA or synthetic compounds such as imidazoquinolines (TLR7/TLR8) (as reviewed by Kawai and Akira [1]). Previous studies have further provided evidence for the involvement of TLR signaling in the induction of autoantibodies [2,3]. Others studies have implicated TLR7 gene duplication in the pathogenesis of autoimmune diseases such as lupus [4,5]. TLR7 is mainly expressed by B cells but also by dendritic cells (DCs), principally plasmacytoid DCs (pDCs). B cells and pDCs appear to have developed specialized mechanisms for enhancing the delivery of potential ligands to TLR7-and TLR9-containing compartments [6]. In view of the pivotal role of (i) DCs in regulating immunity and tolerance [7], (ii) B cells in the C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 46-57 Cellular immune response 47 adaptive immune response, and (iii) regulatory T (Treg) cells in maintaining T-cell tolerance, we evaluated the importance of DC, B-cell, and Treg-cell activation and generation by ligandbound TLR7 in the framework of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). MS is an immune-mediated disease of the central nervous system (CNS), characterized by the infiltration of inflammatory cells, including autoreactive CD4 + T cells and antigen-presenting cells (APCs), which leads to demyelination and axonal damage [8]. Even though CD4 + T-cell autorea...

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Section: Infiltration Of Inflammatory Cells In the Cns Of Tlr7 −/− MIsupporting

confidence: 92%

supporting

confidence: 91%

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TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

et al. 2013

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“…21 Cross-regulation between TLR7 and TLR9 has also been observed in systemic lupus erythematosus. 26,27 Furthermore, deficiency in murine TLR8, a molecule that is considered not to be fully functional in mice, enhances TLR7-mediated responses. 31 It is possible that the regulation is due to competition for shared proteins among TLR7, TLR8, and TLR9.…”

Section: Discussionmentioning

confidence: 99%

“…21,26,27 To examine whether TLR7 influenced TLR9-mediated unresponsiveness in mice, we inoculated wild-type and TLR7-deficient mice with a range of CpG-ODN concentrations. TLR7-deficient mice were more sensitive to CpG-ODN-induced unresponsiveness, with low amounts of CpG-ODN inducing unresponsiveness or death in TLR7-deficient mice but not in wild-type mice ( Figure 13A).…”

Section: Influence Of Tlr7 On Tlr9-mediated Neuroinflammatory Responsesmentioning

confidence: 99%

TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

Butchi

Woods

et al. 2011

The American Journal of Pathology

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Toll-like receptors (TLRs) 7 and 9 recognize nucleic acid determinants from viruses and bacteria and elicit the production of type I interferons and proinflammatory cytokines. TLR7 and TLR9 are similar regarding localization and signal transduction mechanisms. However, stimulation of these receptors has differing effects in modulating viral pathogenesis and in direct toxicity in the central nervous system (CNS). In the present study, we examined the potential of the TLR7 agonist imiquimod and the TLR9 agonist cytosine-phosphateguanosine oligodeoxynucleotide (CpG-ODN) to induce neuroinflammation after intracerebroventricular inoculation. CpG-ODN induced a more robust inflammatory response than did imiquimod after inoculation into the CNS, with higher levels of several proinflammatory cytokines and chemokines. The increase in cytokines and chemokines correlated with breakdown of the bloodcerebrospinal fluid barrier and recruitment of peripheral cells to the CNS in CpG-ODN-inoculated mice. In contrast, TLR7 agonists induced a strong interferon ␤ response in the CNS but only low levels of other cytokines. The difference in response to these agonists was not due to differences in distribution or longevity of the agonists but rather was correlated with cytokine production by choroid plexus cells. These results indicate that despite the high similarity of TLR7 and TLR9 in binding nucleic acids and inducing similar downstream signaling, the neuroinflammation response induced by these receptors differs dramatically due, at least in part, to activation of cells in the choroid plexus.

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RNF115 Inhibits the Post‐ER Trafficking of TLRs and TLRs‐Mediated Immune Responses by Catalyzing K11‐Linked Ubiquitination of RAB1A and RAB13

Zhang

Gan

et al. 2022

Advanced Science

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The subcellular localization and intracellular trafficking of Toll-like receptors (TLRs) critically regulate TLRs-mediated antimicrobial immunity and autoimmunity. Here, it is demonstrated that the E3 ubiquitin ligase RNF115 inhibits the post-endoplasmic reticulum (ER) trafficking of TLRs and TLRs-mediated immune responses by catalyzing ubiquitination of the small GTPases RAB1A and RAB13. It is shown that the 14-3-3 chaperones bind to AKT1-phosphorylated RNF115 and facilitate RNF115 localizing on the ER and the Golgi apparatus. RNF115 interacts with RAB1A and RAB13 and catalyzes K11-linked ubiquitination on the Lys49 and Lys61 residues of RAB1A and on the Lys46 and Lys58 residues of RAB13, respectively. Such a modification impairs the recruitment of guanosine diphosphate (GDP) dissociation inhibitor 1 (GDI1) to RAB1A and RAB13, a prerequisite for the reactivation of RAB proteins. Consistently, knockdown of RAB1A and RAB13 in Rnf115 +/+ and Rnf115 −/− cells markedly inhibits the post-ER and the post-Golgi trafficking of TLRs, respectively. In addition, reconstitution of RAB1A K49/61R or RAB13 K46/58R into Rnf115 +/+ cells but not Rnf115 −/− cells promotes the trafficking of TLRs from the ER to the Golgi apparatus and from the Golgi apparatus to the cell surface, respectively. These findings uncover a common and step-wise regulatory mechanism for the post-ER trafficking of TLRs.

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Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice

Cited by 187 publications

References 58 publications

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

RNF115 Inhibits the Post‐ER Trafficking of TLRs and TLRs‐Mediated Immune Responses by Catalyzing K11‐Linked Ubiquitination of RAB1A and RAB13

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Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice

Cited by 187 publications

References 58 publications

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+Treg cells

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+Treg cells

TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

RNF115 Inhibits the Post‐ER Trafficking of TLRs and TLRs‐Mediated Immune Responses by Catalyzing K11‐Linked Ubiquitination of RAB1A and RAB13

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TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells