Syk is indispensable for CpG-induced activation and differentiation of human B cells

Kremlitzka, Mariann; Mácsik-Valent, Bernadett; Erdei, Anna

doi:10.1007/s00018-014-1806-x

Cited by 19 publications

(19 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This data is consistent with previous reports demonstrating that Syk kinase is essential for mediating NK cell killing function [31]. While a majority of the TLR signaling pathways are mediated by IRAK4 kinase [32], we observed that inhibitors of other kinases such as PI3Kδ, SYK/ZAP-70 and JAK also have an impact on functional TLR responses, consistent with previous reports [33–35]. Among the TLR responses evaluated, cyclosporine, PI3Kδ and SYK/ZAP70 inhibitors inhibited TLR3 and TLR9, but not TLR7 induced responses.…”

Section: Discussionsupporting

confidence: 93%

A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system

et al. 2017

View full text Add to dashboard Cite

While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the ‘immune fingerprint’ of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.

show abstract

Section: Discussionsupporting

confidence: 93%

A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The proximal BCR-signalosome molecules, Syk and Btk, have been associated with TLR7/TLR9 activation (37–39). In human B cells, Syk appears to be a positive regulator of TLR and TLR–BCR synergism, since inhibition of Syk blocks TLR responses (40, 41). The role of Btk in BCR–TLR signaling is less clear.…”

Section: Proximal Bcr-signaling Components Important For Tlr7/tlr9 Aumentioning

confidence: 99%

“…While not yet studied directly in B cells, the molecular mechanism may be similar to that found in dendritic cells, where Lyn directly associates with IRF5 and in doing so, inhibits the ability of TRAF6 to associate with and activate the transcription factor (55). 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).…”

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

confidence: 99%

“…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%

See 1 more Smart Citation

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

Suthers

Sarantopoulos

2017

Front. Immunol.

View full text Add to dashboard Cite

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.

show abstract

“…It has been shown that many signaling pathways induce Syk phosphorylation, such as BCR, TLR, and BAFF signaling pathways [41][42][43][44]. Notably, BCR, TLR, and Bcell activating factor signaling are highly activated in B cells from SLE patients and lupus-prone mice [45][46][47][48].…”

Section: Ifn-α In Sle Pathogenesismentioning

confidence: 99%

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

et al. 2015

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is Keywords: Autophagy B cells Interferon-α STS-1 Systemic lupus erythematosusAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacroautophagy, conventionally referred to as autophagy, is a highly conserved lysosome-mediated catabolic process in which cytoplasmic contents are degraded and recycled [1]. Recently, various autophagic functions have been recognized in innate and adaptive immunity, including pathogen clearance, inflammasome regulation, and maintenance of tolerance [2,3]. The observations Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn of the autophagic functions that trigger or exacerbate autoimmunity show that autophagy participates in the pathogenesis of autoimmune disorders, such as systemic lupus erythematosus (SLE) [4][5][6].SLE is a potentially fatal autoimmune disease that is characterized by B-cell hyperactivation and production of autoantibodies that mainly target nuclear components [7]. Of note, B cells play a central role in the pathogenesis of SLE through the production of pathogenic autoantibodies [8,9]. Enhanced autophagic activities have been observed in B cells from SLE patients and NZB/W F1 mice [5]. Studies have increasingly demonstrated that autophagy C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2378 Guanjun Dong et al. Eur. J. Immunol. 2015. 45: 2377-2388 is involved in B-cell development, homeostasis, activation, and antibody response [10,11]. Because B cells are a major player in SLE, autophagy-mediated modulation of B cells can directly influence the pathophysiology of SLE. In fact, the contribution of autophagy to the pathogenesis of SLE has been supported by the beneficial effects of autophagy modulating molecules on disease development in SLE patients and lupus-prone mice, such as rapamycin and P140 peptide [12,13]. Given that the autophagy pathway can be considered as an effective therapeutic target in the treatment of SLE, the exploration of the enhanced autophagic activity mechanism of B cells during SLE is urgently needed. Autophagy can be provoked by host-derived cytokines, IFN-I/II or pattern recognition receptors in many cell types [2,14,15]. However, to date, the enhanced autophagic activity mechanism in SLE B cells remains unknown, although BCR ligands have been shown to induce autophagy in B cells [16,17]. Of note, IFN-α, a central cytokine in the pathogenesis of SLE, can induce and accelerate SLE symptoms in patients and mice [18]. Importantly, B cells display a significant IFN-I inducible gene signature in SLE patients [19] and IFN-α impacts B-cell functions through a variety of mechanisms, such as TLR7 expression, differentiation, and class-switch recombination [20][21][22]. Importantly, IFN-α provokes autophagy in many different cell types and JAK1-STAT1 signaling plays an absolutely necessary role in this process [23]. However, it remains unknown whether IFN-α can induce autophagy in primary human and murine B cells.ST...

show abstract

Syk is indispensable for CpG-induced activation and differentiation of human B cells

Cited by 19 publications

References 47 publications

A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system

A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system

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

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

Contact Info

Product

Resources

About