Chemokine Receptor 2 Blockade Prevents Asthma in a Cynomolgus Monkey Model

Mellado, Mario; Ana, Ana Martı́n de; Gómez, Lucio; Martı́nez-A, Carlos; Rodrı́guez-Frade, José Miguel

doi:10.1124/jpet.107.128538

Cited by 37 publications

(30 citation statements)

References 39 publications

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“…CCL2 is produced by many cell types, including endothelial cells, fibroblasts, epithelial and smooth muscle cells, monocytes, and microglial cells (27). Increased expression of CCL2 has been reported in asthmatic bronchi (28)(29)(30), and blocking the CCL2-CCR2 axis attenuated the asthma phenotype in other animal models of asthma (31). Here, we show that the expression of CCL2 is rapidly induced in the allergic airway of human subjects with asthma by allergen challenge, suggesting that airway epithelial cells are a likely source of luminal CCL2 induced by signaling through their protease-activated receptors because allergen denaturation with heat partially prevents the secretion of CCL2 from epithelial cells (32).…”

Section: Discussionmentioning

confidence: 99%

Recruited Alveolar Macrophages, in Response to Airway Epithelial–Derived Monocyte Chemoattractant Protein 1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma

Lee

Jeong²,

Nyenhuis

et al. 2015

Am J Respir Cell Mol Biol

151

142

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Although alveolar macrophages (AMs) from patients with asthma are known to be functionally different from those of healthy individuals, the mechanism by which this transformation occurs has not been fully elucidated in asthma. The goal of this study was to define the mechanisms that control AM phenotypic and functional transformation in response to acute allergic airway inflammation. The phenotype and functional characteristics of AMs obtained from human subjects with asthma after subsegmental bronchoprovocation with allergen was studied. Using macrophagedepleted mice, the role and trafficking of AM populations was determined using an acute allergic lung inflammation model. We observed that depletion of AMs in a mouse allergic asthma model attenuates Th2-type allergic lung inflammation and its consequent airway remodeling. In both human and mouse, endobronchial challenge with allergen induced a marked increase in monocyte chemotactic proteins (MCPs) in bronchoalveolar fluid, concomitant with the rapid appearance of a monocyte-derived population of AMs. Furthermore, airway allergen challenge of allergic subjects with mild asthma skewed the pattern of AM gene expression toward high levels of the receptor for MCP1 (CCR2/ MCP1R) and expression of M2 phenotypic proteins, whereas most proinflammatory genes were highly suppressed. CCL2/MCP-1 gene expression was prominent in bronchial epithelial cells in a mouse allergic asthma model, and in vitro studies indicate that bronchial epithelial cells produced abundant MCP-1 in response to house dust mite allergen. Thus, our study indicates that bronchial allergen challenge induces the recruitment of blood monocytes along a chemotactic gradient generated by allergen-exposed bronchial epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Recruited Alveolar Macrophages, in Response to Airway Epithelial–Derived Monocyte Chemoattractant Protein 1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma

Lee

Jeong²,

Nyenhuis

et al. 2015

Am J Respir Cell Mol Biol

151

142

View full text Add to dashboard Cite

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“…In addition, allergen-induced as well as direct CCL2/MCP-1-induced changes in airway hyperreactivity were significantly attenuated in CCR2-deficient mice (25). The blockade of CCR2 by specific antibody led to reduced bronchial hyperresponsiveness and attenuated macrophage and eosinophil accumulations in BAL of a primate model challenged with Ascaris suum (106). These controversial findings regarding the role of CCR2 in asthma/allergic airway diseases may be the result of different allergens used to sensitize the animals, suggesting that, clinically, CCR2 inhibition/stimulation should be considered based on allergens identified.…”

Section: Chemokine Receptors In Chronic Lung Diseasesmentioning

confidence: 99%

Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking

Tománková

Kriegová

Liu

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chemokine receptors and their chemokine ligands, key mediators of inflammatory and immune cell trafficking, are involved in the regulation of both physiological and pathological processes in the lung. The discovery that chemokine receptors/chemokines, typically expressed by inflammatory and immune cells, are also expressed in structural lung tissue cells suggests their role in mediating the restoration of lung tissue structure and functions. Thus, chemokine receptors/chemokines contribute not only to inflammatory and immune responses in the lung but also play a critical role in the regulation of lung tissue repair, regeneration, and remodeling. This review aims to summarize current state-of-the-art on chemokine receptors and their ligands in lung diseases such as chronic obstructive pulmonary disease, asthma/allergy, pulmonary fibrosis, acute lung injury, and lung infection. Furthermore, the therapeutic opportunities of chemokine receptors in aforementioned lung diseases are discussed. The review also aims to delineate the potential contribution of chemokine receptors to the processes leading to repair/regeneration of the lung tissue.

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“…In Schistosoma mansoni -challenged mice, CCL2 production has been found to increase significantly and be accompanied by an influx of leukocyte migration into the lung and subsequent airway hyperreactivity [16]. CCL2 mediates the activation and recruitment of inflammatory cells into the lung by binding to its specific receptor, CCR2 [3,17]. Some studies have explored the relationship between the CCL2/CCR2 axis and inflammatory cells.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies have explored the relationship between the CCL2/CCR2 axis and inflammatory cells. Mellado et al [17 ]found that neutralization of CCR2 attenuated macrophage and eosinophil accumulation in the bronchoalveolar lavage fluid (BALF) of asthmatic monkeys. Lukacs et al [16 ]reported that neutralization of CCL2 significantly reduced total leukocyte migration, especially CD4+ and CD8+ lymphocytes, although it was not clear which T-cell subsets were involved.…”

Section: Introductionmentioning

confidence: 99%

CCL2/CCR2-Dependent Recruitment of Th17 Cells but Not Tc17 Cells to the Lung in a Murine Asthma Model

Wang¹,

Wang²,

Cao³

et al. 2015

Int Arch Allergy Immunol

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Background: Interleukin (IL)-17 has been implicated in the pathogenesis of asthma and the progression of airway inflammation. Here, we used a model of allergic asthma and found that the frequencies of IL-17-secreting T helper (Th)17 and CD8 (Tc)17 cells were both significantly increased, as was the expression of the CC chemokine receptor (CCR2) on the surface of these cells. CC chemokine ligand 2 (CCL2) has been shown to mediate the activation and recruitment of inflammatory cells in asthma, which are also skewed after ovalbumin (OVA) challenge. However, the role of CCL2 on Th17 cells and Tc17 cells in asthma has not been illuminated. Methods: Mice that were sensitized and challenged with OVA received anti-CCL2 antibody (Ab; 5 μg/day intratracheally) or CCR2 antagonist (RS504393, 2 mg/kg/day intraperitoneally) prior to the challenge. Some mice received an isotype control Ab or vehicle alone. We then assessed the effects of allergic asthma and anti-CCL2 Ab or CCR2 antagonist treatment on the levels of IL-17 and CCL2, the Th17 and Tc17 cell frequencies and lung tissue inflammation. Results: We demonstrated that CCL2 and IL-17 levels and the frequency of Th17 and Tc17 cells in lung tissues and bronchoalveolar lavage fluid increased in the asthma group compared with the normal control mice. Blocking the CCL2/CCR2 axis greatly reduced the Th17 but not the Tc17 cell frequency, and revealed a suppressive effect on airway inflammation. Conclusion: These findings indicate a role for the CCL2/CCR2 axis in mediating Th17 but not Tc17 cell migration during acute allergic airway inflammation.

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Chemokine Receptor 2 Blockade Prevents Asthma in a Cynomolgus Monkey Model

Cited by 37 publications

References 39 publications

Recruited Alveolar Macrophages, in Response to Airway Epithelial–Derived Monocyte Chemoattractant Protein 1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma

Recruited Alveolar Macrophages, in Response to Airway Epithelial–Derived Monocyte Chemoattractant Protein 1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma

Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking

CCL2/CCR2-Dependent Recruitment of Th17 Cells but Not Tc17 Cells to the Lung in a Murine Asthma Model

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