Increased Syk phosphorylation leads to overexpression of TRAF6 in peripheral B cells of patients with systemic lupus erythematosus

Iwata, S.; Yamaoka, Kunihiro; Niiro, Hiroaki; Jabbarzadeh-Tabrizi, Siamak; Sp, Wang; Kondo, Masahiro; Yoshikawa, Masahide; Akashi, Koichi; Tanaka, Yoshiya

doi:10.1177/0961203314560424

Cited by 31 publications

(25 citation statements)

References 30 publications

(45 reference statements)

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“…Syk is a positive regulator of TLR signaling (40, 41). Syk activation has been associated with TRAF6 expression in B cells from patients with SLE (38). The association between Syk and TRAF6 suggests an important point of crosstalk in the context of autoimmune disease, suggesting a potential mechanism for how Syk blockade attenuates the TLR9 responses (40).…”

Section: Bcr and Tlr7/tlr9 Signaling Cascades: Crosstalk And Potentiamentioning

confidence: 99%

TLR7/TLR9- and B Cell Receptor-Signaling Crosstalk: Promotion of Potentially Dangerous B Cells

Suthers

Sarantopoulos

2017

Front. Immunol.

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B cells are capable of receptor-mediated responses to foreign antigens. Recognition of microbial-derived nucleic acid (NA) by toll-like receptors (TLRs) 7 and 9 in B cells has been substantiated. Endogenous NA released from damaged or dying cells can also be immunogenic in certain contexts and can incite aberrant activation of B cells. When TLR-driven B cell receptor (BCR)-activated B cells are not properly constrained, pathologic autoantibodies are produced. It is also clear that endosomal TLR7/TLR9 can operate in conjunction with BCR. In addition to BCR signaling, a balance between TLR7 and TLR9 is pivotal in the development of B cell autoreactivity. While TLR9 is important in normal memory B cell responses through BCR, TLR9 activation has been implicated in autoantibody production. Paradoxically, TLR9 also plays known protective roles against autoimmunity by directly and indirectly inhibiting TLR7-mediated autoantibody production. Herein, we summarize literature supporting mechanisms underpinning the promotion of pathological BCR-activated B cells by TLR7 and TLR9. We focus on the literature regarding known points of TLR7/TLR9 and BCR crosstalk. Data also suggest that the degree of TLR responsiveness relies on alterations of certain intrinsic B-cell signaling molecules and is also context specific. Because allogeneic hematopoietic stem cell transplantation is a high NA and B cell-activating factor environment, we conclude that B cell studies of synergistic TLR–BCR signaling in human diseases like chronic graft-versus-host disease are warranted. Further understanding of the distinct molecular pathways mediating TLR–BCR synergy will lead to the development of therapeutic strategies in autoimmune disease states.

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Section: Bcr and Tlr7/tlr9 Signaling Cascades: Crosstalk And Potentiamentioning

confidence: 99%

TLR7/TLR9- and B Cell Receptor-Signaling Crosstalk: Promotion of Potentially Dangerous B Cells

Suthers

Sarantopoulos

2017

Front. Immunol.

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“…Subsequent studies, recently summarized by Suthers and Sarantopoulos 20 , have identified several potential points of communication between TLR signaling pathways and BCR ITAM signaling. For example, one aspect of TLR–BCR crosstalk involves Syk-driven upregulation of the TLR signaling molecule TRAF6 21 . However, this mechanism requires induction of new gene expression, a process that would take minutes to hours and thus cannot account for receptor synergy that occurs within seconds of receptor engagement.…”

Section: Pre-transcriptional Controlmentioning

confidence: 99%

Molecular mechanisms of macrophage Toll-like receptor–Fc receptor synergy

Lennartz

Drake

2018

F1000Res

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Macrophages (MØs) are a key cell type of both the innate and the adaptive immune response and can tailor their response to prevailing conditions. To sense the host’s status, MØs employ two classes of receptors: Toll-like receptors (TLRs), which are sensors for pathogen-derived material, and Fcγ receptors (FcγRs) that are detectors of the adaptive immune response. How MØs integrate the input from these various sensors is not understood and is the focus of active study. Here, we review the recent literature on the molecular mechanisms of TLR and FcgR crosstalk and synergy, and discuss the implications of these findings. This overview suggests a multilayered mechanism of receptor synergy that allows the MØ to fine-tune its response to prevailing conditions and provides ideas for future investigation.

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“…TRAF6 is an E3 ligase which acts as an intermediate signalling adaptor between signals such as pathogen-associated molecular patterns (PAMPs) and downstream pathways including nuclear factor-kB (NF-kb), c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK). TRAF6 is involved in immune responses via the regulation of inflammation [ 16 ], differentiation and proliferation of B cells [ 17 ] and development of medullary thymic epithelial cells [ 18 ]. TRAF6 also is implicated in muscle atrophy [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies

et al. 2016

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BackgroundThe idiopathic inflammatory myopathies (IIM) are autoimmune diseases characterised by acquired proximal muscle weakness, inflammatory cell infiltrates in muscle and myositis-specific/associated autoantibodies. It is unclear which pathways are involved in IIM, and the functional relationship between autoantibody targets has not been systematically explored. Protein-protein interaction and pathway analyses were conducted to identify pathways relevant to disease, using autoantibody targets and gene products of IIM-associated single nucleotide polymorphism (SNP) loci.MethodsProtein-protein interactions were analysed using Disease Association Protein-Protein Link Evaluator (DAPPLE). Gene ontology and pathway analyses were conducted using Database for Annotation Visualisation and Integrated Discovery (DAVID) and Gene Relationships Across Implicated Loci (GRAIL). Analyses were undertaken including the targets of published autoantibodies, significant and suggestive SNPs from an IIM association study and autoantibody targets plus SNPs combined.ResultsThe protein-protein interaction networks formed by autoantibody targets and associated SNPs showed significant direct and/or indirect connectivity (p < 0.05). Autoantibody targets plus associated SNPs combined resulted in more significant indirect and common interactor connectivity, suggesting autoantibody targets and proteins encoded by IIM-associated loci may be involved in common pathways. Tumour necrosis factor receptor-associated factor 6 (TRAF6) was identified as a hub protein, and UBE3B, HSPA1A, HSPA1B and PSMD3 also were identified as genes with significant connectivity. Pathway analysis identified that autoantibody targets and associated SNP regions are significantly interconnected (p < 0.01), and confirmed autoantibody target involvement in translational and post-translational processes. ‘Ubiquitin’ was the only keyword strongly linking significant genes across regions in all three GRAIL analyses of autoantibody targets and IIM-associated SNPs.ConclusionsAutoantibody targets and IIM-associated loci show significant connectivity and inter-relatedness, and identify several key genes and pathways in IIM pathogenesis, possibly mediated via the ubiquitination pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1061-7) contains supplementary material, which is available to authorized users.

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Increased Syk phosphorylation leads to overexpression of TRAF6 in peripheral B cells of patients with systemic lupus erythematosus

Abstract: Our results suggest that the activated Syk-mediated TRAF6 pathway leads to aberrant activation of B cells in SLE, and also highlight Syk as a potential target for B-cell-mediated processes in SLE.

Cited by 31 publications

References 30 publications

TLR7/TLR9- and B Cell Receptor-Signaling Crosstalk: Promotion of Potentially Dangerous B Cells

TLR7/TLR9- and B Cell Receptor-Signaling Crosstalk: Promotion of Potentially Dangerous B Cells

Molecular mechanisms of macrophage Toll-like receptor–Fc receptor synergy

Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies

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