Syk kinase is required for collaborative cytokine production induced through Dectin‐1 and Toll‐like receptors

Dennehy, Kevin M.; Ferwerda, Gerben; Faro-Trindade, Inês; Pyż, Elwira; Willment, Janet A.; Taylor, Philip Russel; Kerrigan, Ann M.; Tsoni, S. Vicky; Gordon, Siamon; Meyer‐Wentrup, Friederike; Adema, Gosse J.; Kullberg, Bart‐Jan; Schweighoffer, Edina; Tybulewicz, Victor L. J.; Mora-Montes, Héctor M.; Gow, Neil A. R.; Williams, David L.; Netea, Mihai G.; Brown, Gordon D.

doi:10.1002/eji.200737741

Cited by 338 publications

(324 citation statements)

References 32 publications

(55 reference statements)

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“…Nevertheless, anti-CLEC-2 mAb treatment combined with Pam3CSK4 (a TLR1/2 agonist) or LPS (a TLR4 agonist) induced increased production of IL-10 by DCs and MØ. This is reminiscent of reports that Dectin-1 and MICL/DCAL-2 engagement can markedly potentiate cytokine production induced by TLR stimulation in myeloid cells [10,11,42,44]. However, a marked difference is that in the case of CLEC-2 this appears to be a qualitative effect that impacts selectively on some cytokine genes but not others.…”

mentioning

confidence: 69%

CLEC‐2 signaling via Syk in myeloid cells can regulate inflammatory responses

et al. 2011

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Myeloid cells express a plethora of C-type lectin receptors (CLRs) that can regulate immune responses. CLEC-2 belongs to the Dectin-1 sub-family of CLRs that possess an extracellular C-type lectin-like domain and a single intracellular hemITAM motif. CLEC-2 is highly expressed on mouse and human platelets where it signals via Syk to promote aggregation. We generated a monoclonal antibody (mAb) against mouse CLEC-2 and found that CLEC-2 is additionally widely expressed on leukocytes and that its expression is upregulated during inflammation. MAb-mediated crosslinking of CLEC-2 leads to hemI-TAM-dependent signaling via Syk, Ca 21 and NFAT and, in myeloid cells, modulates the effect of toll-like receptor (TLR) agonists to selectively potentiate production of IL-10. A macrophage/dendritic cell-dependent increase in IL-10 is also observed in mice given anti-CLEC-2 mAb together with LPS. Collectively, these data indicate that CLEC-2 is expressed in myeloid cells and acts as a Syk-coupled CLR able to modulate TLR signaling and inflammatory responses.Key words: CLEC-2 . C-type lectin . HemITAM . IL-10 . Syk Supporting Information available online IntroductionSignaling by some members of the C-type lectin receptor (CLR) superfamily plays a key role in innate immunity and in regulation of myeloid cell function [1,2]. A classical example is Dectin-1, which is expressed by macrophages (MØs), neutrophils and dendritic cells (DCs) and acts as a pattern recognition receptor for b-glucans present on fungal and some bacterial cell walls. Dectin-1 signals via a phospho-tyrosine-based hemITAM motif in its intracellular domain that recruits spleen tyrosine kinase (Syk) [3,4]. Dectin-1 signaling through Syk in myeloid cells can variably lead to phagocytosis, production of reactive oxygen species (ROS) and/or induction of innate response genes, including those encoding pro-inflammatory cytokines [5,6]. 3040Pro-inflammatory Dectin-1 signaling requires CARD9-dependent activation of NF-kB [7] although Dectin-1 can also signal to NF-kB via a Syk-independent pathway [8]. Although many DC types are potently activated by Dectin-1 agonists, in other myeloid cells Dectin-1 signaling only weakly activates the proinflammatory gene program [9]. In those cells, Dectin-1 acts primarily in synergy with other innate immune receptors such as toll-like receptors (TLRs) [10,11]. Notably, both Dectin-1 and CARD9 are important for resistance to fungal infection in both mice [7,12,13] and humans [14,15], indicating the importance of the CLR/Syk signaling pathway in immunity.The features of Dectin-1, including type II membrane topology, single Dectin-1-like C-type lectin-like domain and intracellular hemITAM are shared by two other CLRs, DNGR-1 (CLEC9A) and CLEC-2 (CLEC1B). DNGR-1 is selectively expressed by DCs and acts as a receptor for dead cells, facilitating cross-priming to cell-associated antigens [16]. CLEC-2 was first identified in a screen for natural killer (NK) cell receptors and its mRNA was found in myeloid cells and in some NK-cell clones [...

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CLEC‐2 signaling via Syk in myeloid cells can regulate inflammatory responses

et al. 2011

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“…131 Dectin-1 is shown to collaborate with TLR2, 4, 5, 7 or 9 to synergistically influence the secretion of many cytokines (inducing IL-23, while repressing IL-12). 132,133 In human PBMCs, Dectin-1/TLR2 pathway was able to amplify MRinduced IL-17 production, a vital cytokine upon C. albicans stimulus. This finding provides an evidence for the interaction between C-type lectin receptors and TLRs.…”

Section: Prrs Of Neutrophils and Monocytes/macrophagesmentioning

confidence: 99%

The role of pattern recognition receptors in the innate recognition ofCandida albicans

Zheng

Wang

et al. 2015

Virulence

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“…Glucan acts via binding to specific receptors such as CR3 or Dectin-1 and via intracellular signaling (Dennehy et al, 2008) thus influencing numerous cell types including monocytes, neutrophils, dendritic cell and NK cells. In addition, glucan manifested significant effects in prevention or modulation of infectious diseases (Renzetti et al, 2009;Ramberg et al, 2010;Novak and Vetvicka, 2008).…”

Section: Introductionmentioning

confidence: 99%

Placebo-Driven Clinical Trials of Transfer Point Glucan #300 in Children With Chronic Respiratory Problems: Iii. Clinical Findings

Větvička

Richter²,

Svozil³

et al. 2013

American Journal of Immunology

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The role of glucan in stimulation of immune reactions has been studied for decades. In this report we focused on the effects of orally administered glucan in children with chronic respiratory problems. We measured the physical endurance using a 6MWT test and the levels of eNO in 50 children aged 8-12 years and evaluated the effects of 100 mg/d oral dose of glucan. We found significant improvements in physical indurance and exhaled nitric oxide in glucan-treated children. In addition, strong improvements in general conditions were found. Short-term oral application of natural immunomodulator β-glucan enhancers the overall health and regulation of energetic metabolism in children with chronic respiratory problems.

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Syk kinase is required for collaborative cytokine production induced through Dectin‐1 and Toll‐like receptors

Cited by 338 publications

References 32 publications

CLEC‐2 signaling via Syk in myeloid cells can regulate inflammatory responses

CLEC‐2 signaling via Syk in myeloid cells can regulate inflammatory responses

The role of pattern recognition receptors in the innate recognition ofCandida albicans

Placebo-Driven Clinical Trials of Transfer Point Glucan #300 in Children With Chronic Respiratory Problems: Iii. Clinical Findings

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