A Critical Role for Eosinophils in Allergic Airways Remodeling

Humbles, Alison A.; Lloyd, Clare M.; McMillan, Scott; Friend, Daniel S.; Xanthou, Georgina; McKenna, Erin E.; Ghiran, Sorina; Gerard, Norma P.; Yu, Channing; Orkin, Stuart H.; Gérard, Craig

doi:10.1126/science.1100283

Cited by 780 publications

(673 citation statements)

References 27 publications

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“…Eosinophils likely play a beneficial role in host defenses against parasitic infections in the human (Klion and Nutman 2004), but have also been implicated in the development and enhancement of inflammation and injury in allergic diseases (Rothenberg and Hogan 2006). Eosinophils secrete a variety of granule-associated pro-inflammatory cytotoxic proteins including major basic protein, eosinophil cationic protein, and eosinophil peroxidase all of which can contribute to airway damage and alterations in airway structure (MacKenzie et al 2001), (Humbles et al 2004). …”

Section: Introductionmentioning

confidence: 99%

Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry

Stevens¹,

Kim²,

Pujanauski

et al. 2007

Journal of Immunological Methods

124

110

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Traditionally, the identification and quantification of eosinophils in inflammatory tissues and exudates has been primarily based upon morphologic criteria and manual counting. In this study, we describe a new flow cytometry-based assay to enumerate eosinophils present in murine bronchoalveolar lavage fluid (BAL) and lung parenchyma obtained from the normal/non-inflamed respiratory tract, following experimentally-induced allergic pulmonary inflammation, and during experimental infection with respiratory syncytial virus (RSV). By using a murine Siglec-F-specific antibody in combination with antibodies directed to CD45 and CD11c, we demonstrate that eosinophils can be distinguished from other cell types in the BAL fluid and lung parenchyma based upon their distinct CD45 + Siglec-F + and CD11c low/− staining profile. In the BAL fluid, this flow cytometry-based method of eosinophil identification/quantitation yields results comparable to the standard morphology-based method without the potential observer bias or staining artifacts inherent in morphology-based quantitation. Furthermore, this flow cytometry-based method can be directly adapted to enumerate eosinophils infiltrating the inflamed lung parenchyma, thereby obviating the need for quantitative morphometry of tissue sections.

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Section: Introductionmentioning

confidence: 99%

Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry

Stevens¹,

Kim²,

Pujanauski

et al. 2007

Journal of Immunological Methods

124

110

View full text Add to dashboard Cite

show abstract

“…Several studies indicate the existence of a mechanism dependent on IL-5 and eosinophils that induce pulmonary damage and intensify AHR [3][4][5]. In other studies, however, the induction of AHR was observed despite the absence of infiltrating eosinophils, suggesting dissociation between these phenomena [6][7][8][9][10]. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule and critical mediator of innate and acquired immune responses [11,12].…”

Section: Introductionmentioning

confidence: 99%

Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation

et al. 2007

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Macrophage migration inhibitory factor (MIF) is increased in asthmatic patients and plays a critical role in the pathogenesis of asthma. We show here that mice lacking MIF failed to develop airway hyper-responsiveness (AHR), tissue eosinophilia, and mucus metaplasia. Analysis of the bronchoalveolar fluids revealed a substantial reduction of IL-13, eotaxin and cysteinyl-leukotrienes. The lack of these cardinal features of asthma in MIF -/-mice occurs regardless of high concentrations of IL-4 in the lung and OVAspecific IgE in the serum. Antigen-specific lymphocyte proliferation and IL-13 production were similarly increased in the draining lymph nodes of OVA-immunized and challenged MIF -/-mice compared to WT, but were reduced in the spleen of MIF -/-, thus indicating differential roles of MIF in these compartments. Stimulation of naive CD4 + cells with anti-CD3 antibody demonstrated that MIF -/-cells produced increased amounts of IFN-c and IL-4 compared to WT CD4 + cells. Finally, treatment of sensitized BALB/c mice with neutralizing anti-MIF antibody abrogated the development of ARH and airway inflammation without affecting the production of Th2 cytokines or IgE. The present study demonstrates that MIF is required for allergic inflammation, adding important elements to our knowledge of asthma pathogenesis and suggesting that neutralization of MIF might be of therapeutic value in asthma. IntroductionAllergic asthma is a disorder characterized by chronic lung inflammation, reversible airway obstruction and increases in airway hyper-responsiveness (AHR) to nonspecific stimuli. Several studies have provided compelling evidences that the lung infiltrating leukocytes and the proinflammatory mediators they produce initiate cellular damage, amplify the immune response, cause airway physiological changes and tissue remodeling [1]. The airway inflammation of asthma has a predominance of Th2 CD4 + lymphocytes, eosinophils and mast cells infiltrating the lung interstitium. Several studies indicate the existence of a mechanism dependent on IL-5 and eosinophils that induce pulmonary damage and intensify AHR [3][4][5]. In other studies, however, the induction of AHR was observed despite the absence of infiltrating eosinophils, suggesting dissociation between these phenomena [6][7][8][9][10]. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule and critical mediator of innate and acquired immune responses [11,12]. Pre-formed MIF protein is present in many cell types and is released in response to different stimuli, such as infection and cytokine stimulation [12]. MIF exhibits several proinflammatory functions, including the induction of TNF-a, IL-1 and NO release from macrophages, and the production of arachidonic acid and eicosanoids through the induction of phospholipase A 2 and cyclooxygenase [13,14]. A unique property of MIF is its secretion by immune cells in response to physiological increase in glucocorticoid levels. Once released, MIF can counterregulate the anti-inflammatory effects of steroids on cyt...

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Section: Introductionmentioning

confidence: 99%

“…It has been shown recently that asthmatic patients that received treatment based on eosinophil counts in sputum had significantly fewer severe asthma exacerbations than patients treated according to standard management therapy [2]. Moreover, genetically modified mice lacking eosinophils are protected against allergen-induced lung injury and asthma [3,4].Although several chemoattractants can mediate eosinophil recruitment, none of them could be identified so far as a predominating factor governing eosinophil infiltration, suggesting a co-operative action of multiple chemoattractants in disease. Among these are the CC-chemokines, such as eotaxin, RANTES, or MCP-4 acting through the chemokine receptor CCR3 [5,6].…”

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confidence: 99%

Hierarchy of eosinophil chemoattractants: role of p38 mitogen‐activated protein kinase

et al. 2006

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Several chemoattractants can regulate the recruitment of eosinophils to sites of inflammation, but the hierarchy among them is unknown. We observed here that eosinophil chemotaxis towards eotaxin or 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) was amplified up to sixfold in the presence of prostaglandin (PG) D 2 . This effect was only seen in eosinophils, and not in neutrophils or basophils. Pretreatment with the chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) antagonist ramatroban prevented the PGD 2 enhancement of eosinophil migrations. In contrast, eotaxin or 5-oxo-ETE inhibited the migration of eosinophils towards PGD 2 . 5-oxo-ETE enhanced the chemotaxis to eotaxin, while eotaxin had no effect on 5-oxo-ETE-induced migration. 5-oxo-ETE induced the phosphorylation of p38 mitogenactivated protein kinase, and inhibition of p38 mitogen-activated protein kinase by SB-202190 converted the effect of 5-oxo-ETE on the chemotaxis to PGD 2 from inhibition to enhancement. The presence of blood or plasma markedly decreased the sensitivity of eosinophils to eotaxin or 5-oxo-ETE, while responses to PGD 2 were unaltered. In conclusion, PGD 2 might be an initial chemoattractant, since it maintains its potency in the circulation and augments the responsiveness of eosinophils to other chemoattractants. In contrast, eotaxin seems to be an end-point chemoattractant, since it has reduced efficacy in blood and is capable of down-modulating eosinophil responsiveness to other chemoattractants. IntroductionAccumulation of eosinophils at sites of allergic reactions, such as eczema or asthma, is associated with tissue injury and lung dysfunction [1]. It has been shown recently that asthmatic patients that received treatment based on eosinophil counts in sputum had significantly fewer severe asthma exacerbations than patients treated according to standard management therapy [2]. Moreover, genetically modified mice lacking eosinophils are protected against allergen-induced lung injury and asthma [3,4].Although several chemoattractants can mediate eosinophil recruitment, none of them could be identified so far as a predominating factor governing eosinophil infiltration, suggesting a co-operative action of multiple chemoattractants in disease. Among these are the CC-chemokines, such as eotaxin, RANTES, or MCP-4 acting through the chemokine receptor CCR3 [5,6]. Prostaglandin (PG) D 2 , a major mast cell mediator released during the allergic response [7] might be of particular importance, since PGD 2 is capable of inducing the chemotaxis of eosinophils, basophils and Th2-type * These authors contributed equally to this study. T cells via a novel receptor, chemoattractant receptorhomologous molecule expressed on TH2 cells (CRTH2) [8,9]. Besides chemotaxis, we have shown that activation of CRTH2 also causes eosinophil respiratory burst and the release of eosinophils from the bone marrow [10]. In vivo, PGD 2 can induce pulmonary eosinophilia [11], and a significant contribution of PGD 2 to the late phase allergi...

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A Critical Role for Eosinophils in Allergic Airways Remodeling

Cited by 780 publications

References 27 publications

Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry

Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry

Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation

Hierarchy of eosinophil chemoattractants: role of p38 mitogen‐activated protein kinase

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