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Multifaceted roles of cysteinyl leukotrienes in eliciting eosinophil granule protein secretion.

Baptista-dos-Reis R, Muniz VS, Neves JS - Biomed Res Int (2015)

Bottom Line: Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1 receptor (cysLT1R) and cysLT2 receptor (cysLT2R).Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins.We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Centro de Ciências da Saúde (CCS), 373 Carlos Chagas Filho Avenue, Room F 14, 1st Floor, Ilha do Fundão, 21941-590 Rio de Janeiro, RJ, Brazil.

ABSTRACT
Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1 receptor (cysLT1R) and cysLT2 receptor (cysLT2R). Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins. Human eosinophils are the main source of cysLTs and are recognized to express both cysLTs receptors (cysLTRs) on their surface, at the plasma membrane. More recently, we identified the expression of cysLTRs in eosinophil granule membranes and demonstrated that cysLTs, acting via their granule membrane-expressed receptors, elicit secretion from cell-free human eosinophil granules. Herein, we review the multifaceted roles of cysLTs in eliciting eosinophil granule protein secretion. We discuss the intracrine and autocrine/paracrine secretory responses evoked by cysLTs in eosinophils and in cell-free extracellular eosinophil crystalloid granules. We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases.

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Related in: MedlinePlus

CysLTs are intracrine signals regulating eosinophils' IL-4 secretion by piecemeal degranulation.IL-4 release induced by IL-16, eotaxin, and RANTES is dependent on the intracrine action of lipid body-generated LTC4. Inhibitors of 5-lypoxigenase (5-LO) and/or cysteinyl leukotriene receptors (cysLTRs) blocked intracellular LTC4 production and consequently IL-4 release from eosinophils. The cross-linking of LIR7- or CD9-induced perinuclear-generated LTC4, however IL-12 secretion induced by LIR7 or CD9 is independent of 5-LO metabolites. CysLT1R = cysLT1 receptor; cysLT2R = cysLT2 receptor, P2Y12R = purinergic P2Y12 receptor, and APLM = arachidonyl phospholipids and lipoxygenase machinery.
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fig1: CysLTs are intracrine signals regulating eosinophils' IL-4 secretion by piecemeal degranulation.IL-4 release induced by IL-16, eotaxin, and RANTES is dependent on the intracrine action of lipid body-generated LTC4. Inhibitors of 5-lypoxigenase (5-LO) and/or cysteinyl leukotriene receptors (cysLTRs) blocked intracellular LTC4 production and consequently IL-4 release from eosinophils. The cross-linking of LIR7- or CD9-induced perinuclear-generated LTC4, however IL-12 secretion induced by LIR7 or CD9 is independent of 5-LO metabolites. CysLT1R = cysLT1 receptor; cysLT2R = cysLT2 receptor, P2Y12R = purinergic P2Y12 receptor, and APLM = arachidonyl phospholipids and lipoxygenase machinery.

Mentions: In eosinophils, it is noteworthy that in addition to their recognized activities as autocrine/paracrine mediators, eicosanoids such as cysLTs are now also recognized to display intracrine effects. The cysLTs, LTC4, and their extracellular derivatives, LTD4 and LTE4, are recognized as paracrine mediators pertinent to asthma and allergic diseases based on their receptor-mediated capabilities to elicit bronchoconstriction, mucous hypersecretion, bronchial hyperresponsiveness, increased microvascular permeability, and additional eosinophil infiltration [1, 15, 18, 37]. Eosinophils are major sources of cysLTs [17] and are the principal LTC4 synthase-expressing cells in bronchial mucosa biopsy specimens from asthmatic subjects, as well as being recognized to express both cysLTRs [1, 17]. Thus, cysLTs are also important autocrine regulators of eosinophil function. Indeed, a series of reports showed that cysLTs have the ability to affect various eosinophil responses [35, 38–41]. For instance, in eosinophils derived from human cord blood progenitors in vitro, it was shown that LTC4, LTD4, and LTE4 induced dose- and time-dependent, vesicular transport-mediated release of preformed IL-4 [38]. Although controversy exists [39], cysLTs also appear to be able to induce the in vitro survival of human eosinophils by activation of cysLT1R [40, 41]. Additionally it was demonstrated that enhanced plasma membrane expression of activation-related CD69 on human eosinophils induced by platelet-activating factor (PAF) and IL-5 is dependent on endogenous eosinophil-derived 5-LO metabolites [35]. Consequently, much interest in understanding the regulation of eicosanoid formation in eosinophils has focused on the mechanisms that regulate eosinophil cysLT formation and release. Interestingly, it was noted that depending on the stimulus, the localized synthesis of LTC4 may occur at distinct intracellular sites within eosinophils (at the perinuclear membrane and/or in lipid bodies) and may control the role of this mediator as either an intracrine signal-transducing mediator that regulates PMD and cytokine secretion or an autocrine/paracrine element in eosinophilic inflammation [2, 32, 36]. In 2002, Bandeira-Melo and colleagues [32] evaluated whether cysLTs function as intracrine mediators involved in the stimulated release of IL-4 from eosinophils. The authors demonstrated that although eotaxin and RANTES each act via CCR3 to stimulate the secretion of both IL-4 and RANTES from eosinophils, only the release of IL-4 was dependent on the activation of 5-LO to form LTC4 within eosinophils' lipid bodies. Inhibitors of 5-LO blocked IL-16-, eotaxin-, and RANTES-induced IL-4 release, but exogenous LTC4, LTD4, and LTE4 did not elicit IL-4 release. Only after membrane permeabilization were cysLTs enabled to enter eosinophils and stimulate IL-4 but not RANTES release. LTC4- and LTD4-elicited IL-4 release was pertussis toxin inhibitable, but inhibitors of the two known GPCRs, cysLT1R and cysLT2R, did not block LTC4-elicited IL-4 release. LTC4 was more potent than LTD4 was and, at low concentrations, elicited IL-4 release from permeabilized eosinophils, whereas higher concentrations were inhibitory probably due to the high-dose inhibition characteristic of the GPCRs. For intact eosinophils, also as a consequence of high intracellular LTC4 levels, LTC4 export inhibitors blocked eotaxin-elicited IL-4 release. Thus, taken together, these data demonstrate that despite being well recognized as an autocrine/paracrine mediator, LTC4, via an intracellular cysLTR distinct from cysLT1R and cysLT2R, may also dynamically govern inflammatory responses as an intracrine mediator of eosinophils' PMD-mediated cytokine secretion (Figure 1).


Multifaceted roles of cysteinyl leukotrienes in eliciting eosinophil granule protein secretion.

Baptista-dos-Reis R, Muniz VS, Neves JS - Biomed Res Int (2015)

CysLTs are intracrine signals regulating eosinophils' IL-4 secretion by piecemeal degranulation.IL-4 release induced by IL-16, eotaxin, and RANTES is dependent on the intracrine action of lipid body-generated LTC4. Inhibitors of 5-lypoxigenase (5-LO) and/or cysteinyl leukotriene receptors (cysLTRs) blocked intracellular LTC4 production and consequently IL-4 release from eosinophils. The cross-linking of LIR7- or CD9-induced perinuclear-generated LTC4, however IL-12 secretion induced by LIR7 or CD9 is independent of 5-LO metabolites. CysLT1R = cysLT1 receptor; cysLT2R = cysLT2 receptor, P2Y12R = purinergic P2Y12 receptor, and APLM = arachidonyl phospholipids and lipoxygenase machinery.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4383494&req=5

fig1: CysLTs are intracrine signals regulating eosinophils' IL-4 secretion by piecemeal degranulation.IL-4 release induced by IL-16, eotaxin, and RANTES is dependent on the intracrine action of lipid body-generated LTC4. Inhibitors of 5-lypoxigenase (5-LO) and/or cysteinyl leukotriene receptors (cysLTRs) blocked intracellular LTC4 production and consequently IL-4 release from eosinophils. The cross-linking of LIR7- or CD9-induced perinuclear-generated LTC4, however IL-12 secretion induced by LIR7 or CD9 is independent of 5-LO metabolites. CysLT1R = cysLT1 receptor; cysLT2R = cysLT2 receptor, P2Y12R = purinergic P2Y12 receptor, and APLM = arachidonyl phospholipids and lipoxygenase machinery.
Mentions: In eosinophils, it is noteworthy that in addition to their recognized activities as autocrine/paracrine mediators, eicosanoids such as cysLTs are now also recognized to display intracrine effects. The cysLTs, LTC4, and their extracellular derivatives, LTD4 and LTE4, are recognized as paracrine mediators pertinent to asthma and allergic diseases based on their receptor-mediated capabilities to elicit bronchoconstriction, mucous hypersecretion, bronchial hyperresponsiveness, increased microvascular permeability, and additional eosinophil infiltration [1, 15, 18, 37]. Eosinophils are major sources of cysLTs [17] and are the principal LTC4 synthase-expressing cells in bronchial mucosa biopsy specimens from asthmatic subjects, as well as being recognized to express both cysLTRs [1, 17]. Thus, cysLTs are also important autocrine regulators of eosinophil function. Indeed, a series of reports showed that cysLTs have the ability to affect various eosinophil responses [35, 38–41]. For instance, in eosinophils derived from human cord blood progenitors in vitro, it was shown that LTC4, LTD4, and LTE4 induced dose- and time-dependent, vesicular transport-mediated release of preformed IL-4 [38]. Although controversy exists [39], cysLTs also appear to be able to induce the in vitro survival of human eosinophils by activation of cysLT1R [40, 41]. Additionally it was demonstrated that enhanced plasma membrane expression of activation-related CD69 on human eosinophils induced by platelet-activating factor (PAF) and IL-5 is dependent on endogenous eosinophil-derived 5-LO metabolites [35]. Consequently, much interest in understanding the regulation of eicosanoid formation in eosinophils has focused on the mechanisms that regulate eosinophil cysLT formation and release. Interestingly, it was noted that depending on the stimulus, the localized synthesis of LTC4 may occur at distinct intracellular sites within eosinophils (at the perinuclear membrane and/or in lipid bodies) and may control the role of this mediator as either an intracrine signal-transducing mediator that regulates PMD and cytokine secretion or an autocrine/paracrine element in eosinophilic inflammation [2, 32, 36]. In 2002, Bandeira-Melo and colleagues [32] evaluated whether cysLTs function as intracrine mediators involved in the stimulated release of IL-4 from eosinophils. The authors demonstrated that although eotaxin and RANTES each act via CCR3 to stimulate the secretion of both IL-4 and RANTES from eosinophils, only the release of IL-4 was dependent on the activation of 5-LO to form LTC4 within eosinophils' lipid bodies. Inhibitors of 5-LO blocked IL-16-, eotaxin-, and RANTES-induced IL-4 release, but exogenous LTC4, LTD4, and LTE4 did not elicit IL-4 release. Only after membrane permeabilization were cysLTs enabled to enter eosinophils and stimulate IL-4 but not RANTES release. LTC4- and LTD4-elicited IL-4 release was pertussis toxin inhibitable, but inhibitors of the two known GPCRs, cysLT1R and cysLT2R, did not block LTC4-elicited IL-4 release. LTC4 was more potent than LTD4 was and, at low concentrations, elicited IL-4 release from permeabilized eosinophils, whereas higher concentrations were inhibitory probably due to the high-dose inhibition characteristic of the GPCRs. For intact eosinophils, also as a consequence of high intracellular LTC4 levels, LTC4 export inhibitors blocked eotaxin-elicited IL-4 release. Thus, taken together, these data demonstrate that despite being well recognized as an autocrine/paracrine mediator, LTC4, via an intracellular cysLTR distinct from cysLT1R and cysLT2R, may also dynamically govern inflammatory responses as an intracrine mediator of eosinophils' PMD-mediated cytokine secretion (Figure 1).

Bottom Line: Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1 receptor (cysLT1R) and cysLT2 receptor (cysLT2R).Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins.We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Centro de Ciências da Saúde (CCS), 373 Carlos Chagas Filho Avenue, Room F 14, 1st Floor, Ilha do Fundão, 21941-590 Rio de Janeiro, RJ, Brazil.

ABSTRACT
Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1 receptor (cysLT1R) and cysLT2 receptor (cysLT2R). Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins. Human eosinophils are the main source of cysLTs and are recognized to express both cysLTs receptors (cysLTRs) on their surface, at the plasma membrane. More recently, we identified the expression of cysLTRs in eosinophil granule membranes and demonstrated that cysLTs, acting via their granule membrane-expressed receptors, elicit secretion from cell-free human eosinophil granules. Herein, we review the multifaceted roles of cysLTs in eliciting eosinophil granule protein secretion. We discuss the intracrine and autocrine/paracrine secretory responses evoked by cysLTs in eosinophils and in cell-free extracellular eosinophil crystalloid granules. We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases.

Show MeSH
Related in: MedlinePlus