Ragweed pollen-mediated IgE-independent release of biogenic amines from mast cells via induction of mitochondrial dysfunction
Introduction
Mast cells are one of the most important effectors involved in elicitation of allergic inflammation and immune responses to many pathogens including parasites (Metcalfe et al., 1997). Antigenic activation of mast cells via the high-affinity receptor for IgE (FcɛRI) mediates exocytosis of cytoplasmic granules containing preformed mediators, secretion of lipid-derived factors, and de novo synthesis of cytokines, chemokines and growth factors (Burgoyne and Morgan, 2003, Logan et al., 2003, Metcalfe et al., 1997, Rivera and Gilfillan, 2006). In addition to FcɛRI-mediated signals, exposure to a variety of stimuli can lead to the release of mast cell mediators (Frossi et al., 2004). Pathogen-associated molecules may activate mast cells and basophils via receptors selectively expressed on their surfaces (Kojima et al., 2007). Eosinophil-derived major basic protein, compound 48/80 or substance P also induces degranulation of mast cells (Munitz et al., 2003). Several lines of evidence indicate that oxidative stress is also a stimulus for mast cell activation (Frossi et al., 2003, Ohmori et al., 1979, Swindle et al., 2002). During allergic and other inflammatory reactions mast cells are exposed to an oxidative microenvironment because ROS are produced by various cell types in the peripheral tissues as a consequence of their effector function (Nagata, 2005). We have previously reported that pollen grains, sub-pollen particles, and pollen extracts contain intrinsic NAD(P)H oxidases, which generate ROS [superoxide anions (O2−)] (Bacsi et al., 2006a, Boldogh et al., 2005). These radicals induce oxidative stress in cultured cells, as well as in airway and conjunctival epithelium within minutes of exposure (Bacsi et al., 2005, Boldogh et al., 2005).
There is a close correlation between the exclusively maternal inheritance of mitochondria and the fact that maternal history of atopy and asthma is one of the substantial risk factors for the development of asthma in children (Litonjua et al., 1998). A mitochondrial haplogroup has been shown to be associated with elevated total serum IgE levels in asthmatic patients (Raby et al., 2007). Oxidative stress and mitochondrial metabolism are involved in antigen-induced release of mast cell mediators, including IL-4, which is essential for naive T cell polarization toward Th2 phenotype (Frossi et al., 2003, Inoue et al., 2008). Studies with metabolic inhibitors have demonstrated a close link between mitochondrial energy production and mast cell degranulation (Johansen, 1987). Furthermore, release of Ca2+ from mitochondria is involved in antigen-induced mast cell degranulation (Suzuki et al., 2006).
Here we report for the first time that treatment with short ragweed (Ambrosia artemisiifolia) pollen extract (RWE) induces elevated mitochondrial ROS (mtROS) production in non-sensitized RBL-2H3 cells, a model of mucosal mast cells (Park and Beaven, 2009, Seldin et al., 1985). We show that increased production of ROS from mitochondrial respiratory complex III, but not intrinsic pollen NAD(P)H oxidase-generated ROS directly, enhances secretion of histamine and serotonin from non-sensitized mast cells. Mitochondrial ROS trigger the release of biogenic amines, but not enzymes such as β-hexosaminidase, via inducing PKC-δ- and microtubule-dependent motility of secretory granules and inhibiting activity of vacuolar H+-ATPase independently from intracellular Ca2+ levels. We demonstrate that mtROS are also able to enhance FcɛRI-mediated IL-4 production of mast cells. These findings may shed light on a new role for mitochondrial dysfunction in the regulation of mast cell activation.
Section snippets
Reagents
All reagents were purchased from Sigma–Aldrich (St. Louis, MO) unless otherwise stated.
Cell cultures
The RBL-2H3 cells were obtained from the American Type Cell Collection and cultured at 37 °C in a humidified atmosphere with 5% CO2 in Minimum Essential Medium containing Earle's salts and l-glutamine (Invitrogen, Carlsbad, CA), supplemented with 10% fetal bovine serum, penicillin (100 U/ml) and streptomycin (100 μg/ml).
Analysis of inflammatory mediator release
Cells were treated with RWE (Greer Laboratories, Lenoir, NC) at the indicated concentrations
RWE induces the release of biogenic amines in an IgE-independent manner
Previous studies have demonstrated that exposure to a variety of non-antigenic stimuli leads to the activation of mast cells (Frossi et al., 2004, Stassen et al., 2002, Yoshimaru et al., 2006). Here we investigated whether RWE induces degranulation of RBL-2H3 cells in the absence of sensitization with IgE antibodies. Treatment of the cells with RWE induced the release of histamine in a dose-dependent manner (Fig. 1A). Administration of RWE (100 μg/ml) to the cells also increased the secretion of
Discussion
Mitochondria are involved in regulation of various cellular functions as they store/release/generate signaling mediators including Ca2+ and ROS. These mediators are required in differentiation and function of various immune cells participating in innate and adaptive responses (Del Prete et al., 2008, Hunt et al., 1991). In this study, we show that increased production of mtROS, induced by treatment with RWE, triggers secretion of biogenic amines, i.e. histamine and serotonin, but not
Acknowledgements
This work was supported by NIAID, P01 AI062885-01 (I.B., S.S., T.H.), NIH HL071163 (S.S., I.B.), NIEHS Center Grant, EOS 006677 and the Hungarian Scientific Research Fund (73347).
References (80)
- et al.
Subpollen particles: carriers of allergenic proteins and oxidases
J. Allergy Clin. Immunol.
(2006) - et al.
Effect of pollen-mediated oxidative stress on immediate hypersensitivity reactions and late-phase inflammation in allergic conjunctivitis
J. Allergy Clin. Immunol.
(2005) - et al.
Localization of superoxide anion production to mitochondrial electron transport chain in 3-NPA-treated cells
Mitochondrion
(2006) - et al.
Intravesicular calcium release mediates the motion and exocytosis of secretory organelles: a study with adrenal chromaffin cells
J. Biol. Chem.
(2008) - et al.
Protein kinase Cdelta functions downstream of Ca2+ mobilization in FcepsilonRI signaling to degranulation in mast cells
J. Allergy Clin. Immunol.
(2004) - et al.
Role of mitochondria and reactive oxygen species in dendritic cell differentiation and functions
Free Radic. Biol. Med.
(2008) - et al.
Cytosolic calcium facilitates release of secretory products after exocytotic vesicle fusion
FEBS Lett.
(1995) - et al.
Interference with oxidative processes inhibits proliferation of human peripheral blood lymphocytes and murine B-lymphocytes
Int. J. Immunopharmacol.
(1991) - et al.
Reactive oxygen species produced up- or downstream of calcium influx regulate proinflammatory mediator release from mast cells: role of NADPH oxidase and mitochondria
Biochim. Biophys. Acta
(2008) - et al.
Understanding exocytosis in immune and inflammatory cells: the molecular basis of mediator secretion
J. Allergy Clin. Immunol.
(2003)
Superoxide radicals as precursors of mitochondrial hydrogen peroxide
FEBS Lett.
The amino-terminal domain of the E subunit of vacuolar H(+)-ATPase (V-ATPase) interacts with the H subunit and is required for V-ATPase function
J. Biol. Chem.
Diphenyleneiodonium prevents reactive oxygen species generation, tyrosine phosphorylation, and histamine release in RBL-2H3 mast cells
Biochem. Biophys. Res. Commun.
Xanthine oxidase-induced histamine release from isolated rat peritoneal mast cells: involvement of hydrogen peroxide
Biochem. Pharmacol.
Mechanism of upregulation of the inhibitory regulator, src-like adaptor protein (SLAP), by glucocorticoids in mast cells
Mol. Immunol.
A common mitochondrial haplogroup is associated with elevated total serum IgE levels
J. Allergy Clin. Immunol.
Mitochondria, oxygen free radicals, disease and ageing
Trends Biochem. Sci.
Molecular regulation of mast cell activation
J. Allergy Clin. Immunol.
Endomembrane proton pumps: connecting membrane and vesicle transport
Curr. Opin. Plant Biol.
Topology of superoxide production from different sites in the mitochondrial electron transport chain
J. Biol. Chem.
Lipid mediators from pollen act as chemoattractants and activators of polymorphonuclear granulocytes
J. Allergy Clin. Immunol.
Differential activation of mast cells by antigens from Trichinella spiralis muscle larvae, adults, and newborn larvae
Vet. Parasitol.
Silver activates mast cells through reactive oxygen species production and a thiol-sensitive store-independent Ca2+ influx
Free Radic. Biol. Med.
Calcium-pH crosstalks in rat mast cells: cytosolic alkalinization, but not intracellular calcium release, is a sufficient signal for degranulation
Br. J. Pharmacol.
Release of secretory products during transient vesicle fusion
Nature
Expression and localization of heat shock proteins in rat basophilic leukemia cells: differential modulation by degranulation, thermal or oxidative stress
Allergy
Purification and characterization of an arginine-specific peptidase from ragweed (Ambrosia artemisiifolia) pollen
Am. J. Respir. Cell Mol. Biol.
Activation of delta-isoform of protein kinase C is required for oxidant-induced disruption of both the microtubule cytoskeleton and permeability barrier of intestinal epithelia
J. Pharmacol. Exp. Ther.
The V-type H+ ATPase: molecular structure and function, physiological roles and regulation
J. Exp. Biol.
ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation
J. Clin. Invest.
Secretory granule exocytosis
Physiol. Rev.
Protein kinase C-alpha and -delta are required for FcalphaR (CD89) trafficking to MHC class II compartments and FcalphaR-mediated antigen presentation
Traffic
Biology and therapeutic potential of the interleukin-4/interleukin-13 signaling pathway in asthma
Am. J. Respir. Med.
Complex I and complex III of mitochondria have common inhibitors acting as ubiquinone antagonists
Biochem. Biophys. Res. Commun.
Quantitative measurement of mast cell degranulation using a novel flow cytometric annexin-V binding assay
Cytometry
Oxidative stress stimulates IL-4 and IL-6 production in mast cells by an APE/Ref-1-dependent pathway
Eur. J. Immunol.
The mast cell: an antenna of the microenvironment that directs the immune response
J. Leukoc. Biol.
Selective activation of Fyn/PI3K and p38 MAPK regulates IL-4 production in BMMC under nontoxic stress condition
J. Immunol.
H2O2 impairs inflammatory mediator release from immunologically stimulated RBL-2H3 cells through a redox-sensitive, calcium-dependent mechanism
Inflamm. Res.
Characterization of proteases, proteins, and eicosanoid-like substances in soluble extracts from allergenic pollen grains
Int. Arch. Allergy Immunol.
Cited by (35)
Allergy and autoimmunity: Share of genetics and environment
2022, Translational Autoimmunity: Autoimmune Disease Associated with Different Clinical FeaturesEffects of biogenic amines on the immune response and immunoregulation mechanism in hemocytes of Litopenaeus vannamei in vitro
2020, Molecular ImmunologyCitation Excerpt :Combining the above research with our results, our hypothesis is that BA may induce cell apoptosis (Ham et al., 2010; Matam et al., 2016; Ouazia et al., 2015), leading to cell lysis, which decreases the total hemocyte count. In addition, we speculate that THC may be reduced by degranulation leading to cell lysis (Chodaczek et al., 2009; Naumova and Sergeeva, 2004; Yoo et al., 2013). The specific reasons need to be further explored.
Hepatic cytochrome P450 metabolism suppressed by mast cells in type 1 allergic mice
2018, Biochemical PharmacologyCitation Excerpt :Mast cells are derived from bone marrow progenitors that migrate into the blood and subsequently into the tissues, where they undergo final maturation [47]. They can be activated by both IgE-dependent and IgE-independent pathways [48,49], and release a large number of pro-inflammatory and immunoregulatory mediators [47]. Two mast cell surface receptors of c-kit and FcεRI mediate activation via innate and adaptive immune mechanisms [50–52].
The inhibitory activity of atractylenolide III, a sesquiterpenoid, on IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA)
2013, Journal of EthnopharmacologyCitation Excerpt :At 25 and 50 mg/kg of AT III, PCA reaction was inhibited by 15% and 42%, respectively. The inhibitory effect of AT Ш was near to that of 10 mg/kg cetrazine (Chodaczek et al., 2009), a typical anti-histamine drug, which was used as a positive control. The rhizomes of Atractylodes japonica Koidz has been used as a herbal medicine for various immune diseases in East Asia for many centuries.
Polyphosphate is a novel pro-inflammatory regulator of mast cells and is located in acidocalcisomes
2012, Journal of Biological ChemistryCitation Excerpt :Mast cell granules are also similar to acidocalcisomes. They are spherical, electron-dense (14), have high concentrations of cations (calcium, magnesium, potassium, sodium, and zinc) and phosphorus (14, 15), and, as acidocalcisomes, have been proposed to possess a proton pump (vacuolar ATPase) (16) and a calcium pump (Ca2+-Mg2+-ATPase) (17) to maintain their acidity and high calcium levels, respectively. Mast cells and blood basophils are associated with pathological conditions such as asthma, allergy, and anaphylaxis (18).
Pollinosis cofactors
2012, Revue Francaise d'Allergologie