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Stimulus strength determines the BTK-dependence of the SHIP1-deficient phenotype in IgE/antigen-triggered mast cells.

ABSTRACT: Antigen (Ag)-mediated crosslinking of IgE-loaded high-affinity receptors for IgE (Fc?RI) on mast cells (MCs) triggers activation of proinflammatory effector functions relevant for IgE-associated allergic disorders. The cytosolic tyrosine kinase BTK and the SH2-containing inositol-5'-phosphatase SHIP1 are central positive and negative regulators of Ag-triggered MC activation, respectively, contrarily controlling Ca²⁺ mobilisation, degranulation, and cytokine production. Using genetic and pharmacological techniques, we examined whether BTK activation in Ship1-/- MCs is mandatory for the manifestation of the well-known hyperactive phenotype of Ship1-/- MCs. We demonstrate the prominence of BTK for the Ship1-/- phenotype in a manner strictly dependent on the strength of the initial Ag stimulus; particular importance for BTK was identified in Ship1-/- bone marrow-derived MCs in response to stimulation with suboptimal Ag concentrations. With respect to MAPK activation, BTK showed particular importance at suboptimal Ag concentrations, allowing for an analogous-to-digital switch resulting in full activation of ERK1/2 already at low Ag concentrations. Our data allow for a more precise definition of the role of BTK in Fc?RI-mediated signal transduction and effector function in MCs. Moreover, they suggest that reduced activation or curtate expression of SHIP1 can be compensated by pharmacological inhibition of BTK and vice versa.

SUBMITTER: Zorn CN

PROVIDER: S-EPMC6195619 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Stimulus strength determines the BTK-dependence of the SHIP1-deficient phenotype in IgE/antigen-triggered mast cells.

Zorn Carolin N CN Simonowski Anne A Huber Michael M

Scientific reports 20181019 1

Antigen (Ag)-mediated crosslinking of IgE-loaded high-affinity receptors for IgE (FcεRI) on mast cells (MCs) triggers activation of proinflammatory effector functions relevant for IgE-associated allergic disorders. The cytosolic tyrosine kinase BTK and the SH2-containing inositol-5'-phosphatase SHIP1 are central positive and negative regulators of Ag-triggered MC activation, respectively, contrarily controlling Ca<sup>2+</sup> mobilisation, degranulation, and cytokine production. Using genetic a ...[more]

PMID: 30341350

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Project description:Mast cells and basophils are central players in allergic reactions triggered by immunoglobulin E (IgE). They have intracellular granules containing allergic mediators (e.g., histamine, serotonin, inflammatory cytokines, proteases and ?-hexosaminidase), and stimulation by IgE-allergen complex leads to the release of such allergic mediators from the granules, that is, degranulation. Mast cells are residents of mucosal surfaces, including those of nasal and oral cavities, and play an important role in the innate defense system. Members of the mitis group streptococci such as Streptococcus oralis, are primary colonizers of the human oral cavity. They produce hydrogen peroxide (H2O2) as a by-product of sugar metabolism. In this study, we investigated the effects of streptococcal infection on RBL-2H3 mast cell/basophil cell line. Infection by oral streptococci did not induce degranulation of the cells. Stimulation of the RBL-2H3 cells with anti-dinitrophenol (DNP) IgE and DNP-conjugated human serum albumin triggers degranulation with the release of ?-hexosaminidase. We found that S. oralis and other mitis group streptococci inhibited the IgE-triggered degranulation of RBL-2H3 cells. Since mitis group streptococci produce H2O2, we examined the effect of S. oralis mutant strain deficient in producing H2O2, and found that they lost the ability to suppress the degranulation. Moreover, H2O2 alone inhibited the IgE-induced degranulation. Subsequent analysis suggested that the inhibition of degranulation was related to the cytotoxicity of streptococcal H2O2. Activated RBL-2H3 cells produce interleukin-4 (IL-4); however, IL-4 production was not induced by streptococcal H2O2. Furthermore, an in vivo study using the murine pollen-induced allergic rhinitis model suggested that the streptococcal H2O2 reduces nasal allergic reaction. These findings reveal that H2O2 produced by oral mitis group streptococci inhibits IgE-stimulated degranulation by inducing cell death. Consequently, streptococcal H2O2 can be considered to modulate the allergic reaction in mucosal surfaces.

Project description:Mast cells (MCs) are granular cells of the innate immune system which develop from CD34+/CD117+ progenitors and play a role in orchestrating adaptive immune responses. They have a well-known role in allergic reactions following immunoglobulin (Ig)E-mediated activation of the cell-surface expressed IgE high-affinity receptor (Fc?RI). MCs can also respond to various other stimuli due to the expression of a variety of receptors including toll-like receptors (TLRs), immunoglobulin (IgG) receptors (Fc?R), complement receptors such as C5a (CD88) expressed by skin MCs, neuropeptides receptors including nerve growth factor receptor, (NGFR), cytokines receptors such as (IL)-1R and IL-3R, and chemokines receptors including CCR-1 and CCR-3. MCs release three groups of mediators upon degranulation differentiated according to their chemical composition, storage, and time to release. These include preformed mediators (mainly histamine, tryptase, and chymase), de novo synthesized mediators such as prostaglandin (PG)D2, leukotriene (LT)B4 and LTD4, and cytokines including IL-1?, IL-3, tumor necrosis factor (TNF)?, and transforming growth factor(TGF)-?. Emerging evidence indicates a role for IgE-independent MC activation in the late-stage asthmatic response as well as in non-allergic airway diseases including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. MC infiltration/activation has been reported in some, but not all, studies of lung cancer. MC-derived TNF-? possesses tumor-suppressive activity while IL-1? supports tumor progression and metastasis. In IPF lungs, an increase in density of tryptase- and chymase-positive MCs (MCTC) and overexpression of TGF-? support the fibrosis progression. MC-derived chymase activates latent TGF-? that induces the differentiation of fibroblasts to matrix-producing myofibroblasts. In summary, increasing evidence highlights a critical role of MCs in non-allergic diseases that may indicate new approaches for therapy.

Dataset Information

Stimulus strength determines the BTK-dependence of the SHIP1-deficient phenotype in IgE/antigen-triggered mast cells.

Publications

Stimulus strength determines the BTK-dependence of the SHIP1-deficient phenotype in IgE/antigen-triggered mast cells.

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