CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion

Sanjuán, Miguel A. F.; Rao, Navin; Lai, Kuei-Tai A.; Gu, Yin; Sun, Siquan; Fuchs, Anja; Fung-Leung, Wai-Ping; Colonna, Marco; Karlsson, Lars

doi:10.1084/jem2034oia13

Cited by 3 publications

(4 citation statements)

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“…The pathway involved in the recognition of circulating nucleosomes is therefore different from the classical pathway involved in the recognition of CpG‐ODN. The fact that CpG motifs are not involved indicates that nucleosome recognition does not occurs via a CpG‐induced but TLR9‐independent mechanism 31. Importantly, similar results were obtained when we activated normal PMN with SLE plasma, whereas nucleosome‐depleted lupus plasma was not stimulatory, showing that the activation was specifically mediated by circulating nucleosomes.…”

Section: Discussionsupporting

confidence: 72%

Nucleosome‐induced neutrophil activation occurs independently of TLR9 and endosomal acidification: Implications for systemic lupus erythematosus

et al. 2011

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The nucleosome is a major autoantigen known to activate PMN in systemic lupus erythematosus (SLE). TLR9 recognizes bacterial and even mammalian DNA under certain circumstances. Nevertheless, the role of TLR9 in SLE development is still unclear. Since nucleosomes are composed of DNA, we investigated whether TLR9 is required for nucleosome-induced PMN activation. Isolated neutrophils were cultured with nucleosomes, plasma from lupus patients and other stimuli in the presence/absence of various inhibitors. Cells were analyzed by flow cytometry, ELISA and confocal microscopy. We found that nucleosomes circulating in lupus plasma induce the secretion of pro-inflammatory cytokines by PMN. Nucleosomes activate human PMN independently of unmethylated CpG sequences in nucleosomal DNA, leading to IL-8/IL-6/TNF secretion and CD11b up-regulation. Nucleosomes accumulate in the cytoplasm of PMN upon endocytosis, induce TLR9 up-regulation and act synergistically with TLR9 ligands. Nucleosomeinduced activation was not inhibited by polymyxin B (PB), chloroquine (CQ), ammonium chloride (AC) or a TLR9 antagonist. Moreover, both PMN isolated from WT and TLR9-KO mice were activated by nucleosomes, as detected by MIP-2 secretion and CD11b upregulation. Activation occurred therefore independently of endotoxins, endosomal acidification, TLR9 and CpG motifs. TLR9 may thus be differently required in the triggering of nucleosome-induced innate immunity and anti-nucleosome B-cell autoimmunity.Key words: Cell activation . Inflammation . Neutrophils . Nucleosomes . Systemic lupus erythematosus Supporting Information available online IntroductionSystemic lupus erythematosus (SLE) is a rheumatic autoimmune disease of unknown etiology. It is a systemic inflammatory disease characterized by the production of numerous autoantibodies (autoAbs). Upon binding to their target autoantigens (autoAgs), the resulting immune complexes deposit into tissues causing inflammation and damages.The nucleosome is a major lupus autoAg composed of dsDNA and histones. Circulating nucleosomes are present in the blood of SLE patients [1] and increased concentrations are associated with the development of nervous and renal manifestations [2]. Nucleosome-restricted autoAb [3] and nucleosome-specific autoreactive T-helper lymphocytes [4] are also observed in SLE patients and the former strongly correlate with disease activity scores [5]. It is therefore believed that circulating nucleosomes trigger the production of anti-nucleosome, anti-histone and antidsDNA autoAb (a disease marker in SLE), although the exact mechanisms leading to anti-nucleosome autoimmunity are not completely elucidated. PMN are the first cells recruited at inflammation sites. Upon inappropriate activation, PMN-derived reactive species may induce tissue damages and may alter self-antigens. PMN are activated in SLE patients [6,7], especially during active disease, and secrete IL-8 (CXCL8), the concentration of which correlates to disease activity [8]. Importantly, PMN have been suggested to link the i...

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Section: Discussionsupporting

confidence: 72%

Nucleosome‐induced neutrophil activation occurs independently of TLR9 and endosomal acidification: Implications for systemic lupus erythematosus

et al. 2011

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“…We demonstrated that Syk directly associates with TLRs (TLR3, TLR4, and TLR9) and various downstream adaptor molecules and kinases, including MyD88, TRIF, TRAF3, TRAF6, TAK1, and TBK1. Previous studies showed that Syk is recruited to activated TLR4 and TLR9 (23,25). Here, we examined whether Syk was involved in determining the balance between inflammatory and antiinflammatory responses.…”

Section: Discussionmentioning

confidence: 97%

“…Several studies demonstrated that TLR ligands, such as polyinosinicpolycytidylic acid [poly(I:C)], LPS, lipoprotein, CpG (9,(22)(23)(24)(25)(26)(27), and minimally oxidized low-density lipoprotein (LDL) (28,29), as well as factors such as TNF-a (30)(31)(32), can activate Syk. Activation of cells with LPS and minimally oxidized LDL enables Syk to interact with TLR4 (33)(34)(35), MyD88, TRIF (36), and TRAF6 (37).…”

Section: Introductionmentioning

confidence: 99%

The Tyrosine Kinase Syk Differentially Regulates Toll-like Receptor Signaling Downstream of the Adaptor Molecules TRAF6 and TRAF3

et al. 2013

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Toll-like receptors (TLRs) are a major family of pattern recognition receptors, and they play a crucial role in innate immune responses. Activation of TLR4 signaling at the plasma membrane by its ligand lipopolysaccharide (LPS) stimulates a proinflammatory pathway dependent on the E3 ubiquitin ligase TRAF6 (tumor necrosis factor receptor-associated factor 6) and the kinase TAK1 (transforming growth factor β-activated kinase 1), whereas TLR4 signaling at endosomes stimulates the production of type I interferons (IFNs) through a pathway that depends on TRAF3 and the kinase TBK1 (TANK-binding kinase-1). We found that the nonreceptor tyrosine kinase Syk partially mediated the endocytosis of TLR4, but it also played a dual role in TLR4-mediated signaling. LPS-dependent stimulation of TLR4 in Syk-deficient macrophages led to enhanced activation of TAK1 and increased production of proinflammatory cytokines compared to that in wild-type macrophages. In contrast, Syk-deficient macrophages exhibited decreased TLR4-dependent activation of TBK1 signaling and production of type I IFNs. We found that Syk was present in both TRAF6- and TRAF3-containing signaling complexes; however, the LPS-dependent, lysine 63-linked ubiquitination of TRAF6 and TRAF3 was oppositely regulated by Syk. We identified the domains of Syk that interacted with TRAF3, TRAF6, TAK1, and TBK1, factors activated by multiple TLRs, which suggests that Syk may act as a common regulator of various TLR responses. Together, our results demonstrate the opposing regulatory roles of Syk in TLR-mediated TRAF6 and TRAF3 signaling pathways, which suggests that Syk may fine-tune the innate immune response to lessen inflammation.

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“…The TLR‐signalling adaptors, Mal and Myd88, can be tyrosine‐phosphorylated by PTK 14, 15, suggesting that ITAM and ITIM play a regulatory role in TLR‐mediated responses to pathogens, but in what molecular context? Interestingly, DAP12 encodes a consensus ITIM "SPYQEL" within the ITAM, centred about the membrane proximal tyrosine (Table 1).…”

Section: Closet Itim?mentioning

confidence: 99%

You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling

2006

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Paradigms of protein tyrosine kinase (PTK)‐mediated immunoreceptor signalling have developed largely from studies of molecules containing immunoreceptor tyrosine‐based activation motifs (ITAM) and immunoreceptor tyrosine‐based inhibition motifs (ITIM). In some circumstances, ITAM can mediate inhibition and ITIM can propagate activation signals. In addition to classical immune cells, some ITAM‐ and ITIM‐encoding proteins are more widely expressed and are crucial to the development of haemopoietic cells, like osteoclasts and natural killer cells, as well as tissues such as bone and brain. Closer analysis of activating proteins reveals that some potentially encode ITIM within an ITAM. These ‘closet’ ITIM could, under conditions of partial ITAM phosphorylation, mediate inhibitory signalling.

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CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion

Abstract: "CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion

Cited by 3 publications

References 34 publications

Nucleosome‐induced neutrophil activation occurs independently of TLR9 and endosomal acidification: Implications for systemic lupus erythematosus

Nucleosome‐induced neutrophil activation occurs independently of TLR9 and endosomal acidification: Implications for systemic lupus erythematosus

The Tyrosine Kinase Syk Differentially Regulates Toll-like Receptor Signaling Downstream of the Adaptor Molecules TRAF6 and TRAF3

You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling

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