Dectin-1 Stimulation Selectively Reinforces LPS-driven IgG1 Production by Mouse B Cells

Transmembrane adaptor proteins are molecules specialized in recruiting cytoplasmic proteins to the proximity of the cell membrane as part of the signal transduction process. A member of this family, SLP65/SLP76, Csk-interacting membrane protein (SCIMP), recruits a complex of SLP65/SLP76 and Grb2 adaptor proteins, known to be involved in the activation of PLC␥1/2, Ras, and other pathways. SCIMP expression is restricted to antigen-presenting cells. In a previous cell line-based study, it was shown that, in B cells, SCIMP contributes to the reverse signaling in the immunological synapse, downstream of MHCII glycoproteins. There it mainly facilitates the activation of ERK MAP kinases. However, its importance for MHCII glycoprotein-dependent ERK signaling in primary B cells has not been analyzed. Moreover, its role in macrophages and dendritic cells has remained largely unknown. Here we present the results of our analysis of SCIMP-deficient mice. In these mice, we did not observe any defects in B cell signaling and B cell-dependent responses. On the other hand, we found that, in dendritic cells and macrophages, SCIMP expression is up-regulated after exposure to GM-CSF or the Dectin-1 agonist zymosan. Moreover, we found that SCIMP is strongly phosphorylated after Dectin-1 stimulation and that it participates in signal transduction downstream of this important pattern recognition receptor. Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 because of an increased expression and sustained phosphorylation lasting at least 24 h after signal initiation.Dectin-1 is a pattern recognition receptor from the C-type lectin receptor family (1). It is expressed in macrophages, dendritic cells, neutrophils, and a subset of T and B cells (2-4). Through its carbohydrate recognition domain, it specifically recognizes ␤-1,3-glucan (5), which is a typical component of fungal cell walls (6). Dectin-1 is considered a major receptor for ␤-glucans and plays an important role in the defense against various species of pathogenic fungi in mice, including Candida albicans, Aspergillus fumigatus, and Pneumocystis carinii (7-11). The importance of dectin-1 for antifungal defense has also been demonstrated by studies of human patients with disrupted dectin-1 function who display increased mucosal colonization with Candida species and suffer from recurrent mucocutaneous fungal infections (12, 13).Dectin-1 signaling is initiated by phosphorylation of the hemITAM motif in its intracellular tail, leading to the recruitment and activation of the protein tyrosine kinase Syk. This is followed by sequential activation of PLC␥2 and PKC␦. Stimulation of this pathway as well as of additional Syk-independent pathways results in the activation of the transcription factors NF-B, nuclear factor of activated T cells (NFAT), and IRF1/5 and initiation of signaling by the MAP kinases ERK, p38, and JNK, which then contribute to downstr...

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“…All media were supplemented with 10% fetal calf serum and antibiotics. The cells were cultured at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…It is expressed in macrophages, dendritic cells, neutrophils, and a subset of T and B cells (2)(3)(4). Through its carbohydrate recognition domain, it specifically recognizes ␤-1,3-glucan (5), which is a typical component of fungal cell walls (6).…”

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confidence: 99%

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

Králová

Fabišik

Pokorná

et al. 2016

Journal of Biological Chemistry

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“…Macrophages, DCs, neutrophils, natural killer cells, and innate lymphoid cells play major roles in pathogen recognition through specialized receptors such as PRRs (Akira et al, 2006;Shim and Lee, 2015;Seo et al, 2013). Viral infection activates danger signals which are transmitted via PRRs, including TLRs, nucleotide-binding oligomerization domain-like receptors (NLRs), retinoic acid-inducible gene 1-like receptors (RLRs), C-type lectin receptors, cytosolic DNA sensors, and inflammasome signaling cascades.…”

Section: Discussionmentioning

confidence: 99%

Human β-defensin 2 is involved in CCR2-mediated Nod2 signal transduction, leading to activation of the innate immune response in macrophages

Yang

Jang

2019

Immunobiology

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Beta-defensins contribute to host innate defense against various pathogens, including viruses, although the details of their roles in innate immune cells are unclear. We previously reported that human β-defensin 2 (HBD 2) activates primary innate immunity against viral infection and suggested that it plays a role in the induction of the adaptive immune response. We analyzed the mechanisms by which HBD 2 primes innate antiviral immunity and polarized activation of macrophage-like THP-1 cells using the receptor-binding domain (RBD) of Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein (S RBD) as a model antigen. The expression of nucleotide-binding oligomerization domain containing 2 (Nod2), type I interferons, (IFNs), and proinflammatory mediators was enhanced in S RBD-HBD 2-treated THP-1 cells. S RBD-HBD 2 treatment also enhanced phosphorylation and activation of receptor-interacting serine/threonine-protein kinase 2 and IFN regulatory factor 3 compared to S RBD alone. Finally, HBD 2-conjugated S RBD interacted with C-C chemokine receptor 2 (CCR2), and Nod2 was involved in HBD 2-mediated CCR2 signaling, which was associated with the activation and M1 polarization of THP-1 cells. Therefore, HBD 2 promotes CCR2-mediated Nod2 signaling, which induces production of type I IFNs and an inflammatory response, and enhances primary innate immunity leading to an effective adaptive immune response to HBD 2-conjugated antigen.

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“…In this study, dietary supplementation with β-glucan stimulated the proliferative activity of T and B cells. β-glucan exerts a direct effect by binding with glucan receptors on the surface of B cells (human and mouse B cells express Dectin-1) and T cells (αβ T cell receptors – αβ TCRs) to induce a cascade reaction and activate the NF-κB transcription factor [ 96 – 100 ]. NF-κB induces the expression of cytokines, mostly IL-2 and IL-4, which stimulate the proliferation of B and T cells [ 101 , 102 ].…”

Section: Discussionmentioning

confidence: 99%

Reactivity of the immunological system of rats stimulated with Biolex-Beta HP after cyclophosphamide immunosuppression

Wójcik¹

2014

cejoi

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The objective of this study was to determine the stimulating effect of the Biolex-Beta HP (β-1,3/1,6-D-glucan) dietary supplement on selected parameters of specific and non-specific humoral and cellular immunity in rats immunosuppressed with cyclophosphamide. The experimental material comprised 40 Wistar rats, divided into two equal groups: control and experimental. In the course of 3 successive days, the rats from the experimental group were administered cyclophosphamide intramuscularly at a rate of 50 mg/kg BW per day. On the 8th day of the experiment, 10 control and 10 experimental rats were sacrificed, and total protein and γ-globulin levels, lysozyme and ceruloplasmin activity were determined in the blood serum. The proliferative response of blood lymphocytes after stimulation with lipopolysaccharide or concanavalin A, respiratory burst activity and the potential killing activity of phagocytes were determined in whole heparinised blood. Starting on the 8th day of the experiment, the feed of the remaining rats from the experimental and control groups was supplemented for 14 consecutive days with Biolex-Beta HP at a rate of 50 mg/kg BW per day. On day 22, arterial blood samples were collected and immune parameters were determined. The results indicate that β-1,3/1,6-D-glucan has a positive effect on the analysed parameters of non-specific cellular and humoral immunity after cyclophosphamide-induced suppression. Nevertheless, the observed effect only marked a return to the norm, as most of the analysed parameters were merely restored to their initial levels, with the exception of lysozyme activity, which considerably exceeded the level noted before immunosuppression.

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Dectin-1 Stimulation Selectively Reinforces LPS-driven IgG1 Production by Mouse B Cells

Cited by 18 publications

References 33 publications

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

Human β-defensin 2 is involved in CCR2-mediated Nod2 signal transduction, leading to activation of the innate immune response in macrophages

Reactivity of the immunological system of rats stimulated with Biolex-Beta HP after cyclophosphamide immunosuppression

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