Novel association between vasoactive intestinal peptide and CRTH2 receptor in recruiting eosinophils: A possible biochemical mechanism for allergic eosinophilic inflammation of the airways
We explored the relation between vasoactive intestinal peptide (VIP), CRTH2, and eosinophil recruitment. It is shown that CRTH2 expression by eosinophils from allergic rhinitis (AR) patients and eosinophils cell line (Eol-1 cells) was up-regulated by VIP treatment. This was functional and resulted into exaggerated migratory response of cells against PGD2. Nasal challenge of AR patients resulted into significant increase of VIP contents in nasal secretion (ELISA), and the immunohistochemical studies of allergic nasal tissues, showed significant expression of VIP in association with intense eosinophil recruitment. Biochemical assays showed that VIP-induced eosinophils chemotaxis from AR patients and Eol-1 cells, was mediated through CRTH2 receptor. Cells migration against VIP was sensitive to protein kinase C (PKC) and protein kinase A (PKA) inhibition, but not to tyrosine kinase or P38 MAP-kinase inhibition, or calcium chelation. Western blot demonstrated a novel CRTH2 mediated cytosol to membrane translocation of PKC-ε, PKC-δ and PKA-α, γ and IIα reg in Eol-1 cells upon stimulation with VIP. Confocal images and FACS demonstrated a strong association and co-localization between VIP peptide and CRTH2 molecules. Further, VIP induced PGD2 secretion from eosinophils. Our results demonstrate the first evidence of association between VIP and CRTH2 in recruiting eosinophils.
Available from: PubMed Central
- "Either infection-elicited or oxLDL-driven MCP1, for instance, besides its known CCR2-driven chemotactic function, appear as a key activator of lipid body biogenic and leukotriene synthesizing machineries within macrophagic cells (Pacheco et al., 2007; Silva et al., 2009). Once more specifically regarding eosinophils, synergistic effects on eliciting eosinophil chemotaxis have been also described between PGD2 and at least the cytokines IFN-γ and TNF-α (El-Shazly et al., 2011), as well as, between DP2 activation and vasoactive intestinal peptide VIP (El-Shazly et al., 2013). Moreover, RANTES, IL-16 and MIF are also proteic mediators capable of activating eicosanoid synthesizing machinery within eosinophils culminating with the generation of LTC4 and PGD2, that in turn intracrinally or autocrinally mediate eosinophil secretory functions (Bandeira-Melo et al., 2002b,c; Vieira-de-Abreu et al., 2011). "
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ABSTRACT: Eosinophils are effector cells that migrate toward several mediators released at inflammatory sites to perform their multiple functions. The mechanisms driving eosinophil selective accumulation in sites of allergic inflammation are well-established and involve several steps controlled by adhesion molecules, priming agents, chemotactic, and surviving factors. Even though the majority of studies focused on role of protein mediators like IL-5 and eotaxins, lipid mediators also participate in eosinophil recruitment and activation. Among the lipid mediators with distinguish eosinophil recruitment and activation capabilities are platelet activating factor and the eicosanoids, including leukotriene B4, cysteinyl leukotrienes, and prostaglandin D2. In this review, we focused on the role of these four lipid mediators in eosinophil recruitment and activation, since they are recognized as key mediators of eosinophilic inflammatory responses.
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ABSTRACT: Asthma is frequently caused and/or exacerbated by sensitization to fungal allergens, which are ubiquitous in many indoor and outdoor environments. Severe asthma with fungal sensitization is characterized by airway hyperresponsiveness and bronchial constriction in response to an inhaled allergen that is worsened by environmental exposure to airborne fungi and which leads to a disease course that is often very difficult to treat with standard asthma therapies. As a result of complex interactions among inflammatory cells, structural cells, and the intercellular matrix of the allergic lung, patients with sensitization to fungal allergens may experience a greater degree of airway wall remodeling and progressive, accumulated pulmonary dysfunction as part of the disease sequela. From their development in the bone marrow to their recruitment to the lung via chemokine and cytokine networks, eosinophils form an important component of the inflammatory milieu that is associated with this syndrome. Eosinophils are recognized as complex multi-factorial leukocytes with diverse functions in the context of allergic fungal asthma. In this review, we will consider recent advances in our understanding of the molecular mechanisms that are associated with eosinophil development and migration to the allergic lung in response to fungal inhalation, along with the eosinophil's function in the immune response to and the immunopathology attributed to fungus-associated allergic pulmonary disease.
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ABSTRACT: Prostaglandin D2 (PGD2 ) plays an important role in allergic inflammation. The PGD2 receptor, CRTH2, is expressed on basophils, eosinophils, and Th2 lymphocytes and mediates chemotactic activity.
To define the role of CRTH2 in allergen-induced nasal responses in a mouse model of allergic rhinitis (AR), a potent, selective CRTH2 receptor antagonist, ARRY-063 was administered in a model of allergic rhinitis in mice.
ARRY-063 was administered orally to ovalbumin (OVA) sensitized and challenged mice. To assess nasal obstruction, respiratory frequency (RF) was monitored by whole body plethysmography immediately after the 4(th) challenge (early-phase response, EPR) and 24 hrs after the 6(th) challenge (late-phase response, LPR). Nasal resistance (RNA ) was also measured in the LPR. PGD2 was administered with or without OVA to determine the effect of PGD2 on nasal responsiveness. Cytokine levels and histopathological changes in nasal tissue were analyzed.
Instillation of PGD2 in the nose of sensitized mice together with a low concentration of OVA induced both an EPR and LPR. Treatment with the CRTH2 receptor antagonist prevented the decreases in RF seen immediately following the 4(th) challenge of sensitized mice (EPR). In the LPR, decreases in RF and increases in RNA were also prevented by antagonist treatment associated with reduced cytokine levels and inflammation in nasal tissues.
These data identify PGD2 as a mediator of both the EPR and LPR in this model of AR and suggest that antagonism of CRTH2 prevents development of both the EPR and LPR as well as nasal inflammation. This article is protected by copyright. All rights reserved.
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