Ablation of eosinophils leads to a reduction of  allergen-induced pulmonary pathology

Justice, J. Paul; Borchers, Michael T.; Crosby, Jeff; Hines, E.M.; Shen, Huahao; Ochkur, Sergei I.; McGarry, Michael P.; Lee, Nancy A.; Lee, James J.

doi:10.1152/ajplung.00260.2002

Cited by 94 publications

(65 citation statements)

References 36 publications

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“…In our chronic model of allergic airway disease, we observed impaired allergen-induced recruitment of eosinophils, macrophages, and lymphocytes. Our data showing that murine CCR3 is predominantly expressed by eosinophils are consistent with previous studies (19,20). These observations suggest that leukocyte recruitment in chronic allergic inflammation is orchestrated, at least in part, via CCR3 signaling in eosinophils, although we cannot exclude signal transduction events in other cells such as basophils and epithelial cells, because they have been shown to express low levels of CCR3 at least in the human system (21,22).…”

Section: Discussionsupporting

confidence: 91%

“…To define a causative relationship between the recruitment of eosinophils and the onset or progression of pulmonary pathologies associated with allergic asthma, multiple experimental approaches have been used to deplete animals of eosinophils, including manipulation of cytokine (e.g., IL-5 and eotaxins) levels via gene targeting and neutralizing antibodies and depletion of eosinophils using an anti-CCR3 antibody (19,20,(33)(34)(35). More recently, Lee et al (6) targeted the depletion of eosinophils (these mice are designated as PHIL) using an eosinophil-specific promoter to drive expression of a cytocidal protein, diphtheria toxin A.…”

Section: Discussionmentioning

confidence: 99%

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A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Fulkerson

Fischetti

McBride

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

193

173

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To clarify the role and regulation of eosinophils, we subjected several key eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in eosinophil development (⌬dbl-GATA) and eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1͞2 double knockout)] were subjected to Aspergillus fumigatus-induced allergic airway inflammation. Allergen-induced eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1͞2 double knockout, CCR3 knockout, and ⌬dbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of eosinophil-and CCR3-deficient mice. The absence of eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was eosinophil-and CCR3-dependent; pathways downstream from eosinophils were identified, including in situ activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that eosinophils via CCR3 have a central role in chronic allergic airway disease.allergy ͉ asthma ͉ chemokine ͉ cytokine

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Fulkerson

Fischetti

McBride

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

193

173

View full text Add to dashboard Cite

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“…This strategy has been successfully used using anti-CCR3 treatment and in CCR3 Ϫ/Ϫ mice, reducing eosinophilia and the corresponding airway hyperreactivity. 28,29 It may be that different CCR3 ligands are important for various stages of eosinophil migration and/or activation within the airway. Interestingly, the anti-CCL28-treated animals had reduced peribronchial eosinophil accumulation but we could neither find significant evidence of reduced airway eosinophil accumulation nor reduced activation parameters (LTC 4 ) within BAL fluid samples.…”

Section: Discussionmentioning

confidence: 99%

Temporal Production of CCL28 Corresponds to Eosinophil Accumulation and Airway Hyperreactivity in Allergic Airway Inflammation

John¹,

Thomas²,

Berlin³

et al. 2005

The American Journal of Pathology

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CCL28 is a recently identified chemokine ligand for CCR10 and CCR3 that has been identified in mucosal epithelial surfaces in diverse tissues. CCL28-mediated eosinophil chemotaxis and peroxidase release were inhibited by preincubation of cells with anti-CCR3. CCL28 was constitutively expressed in lung tissue collected from nonsensitized control mice but increased levels were found in mice sensitized and rechallenged with cockroach antigen (CRA). CCL28 levels peaked in the lungs 24 hours after intratracheal challenge with CRA, whereas eotaxin expression peaked at 8 hours. Increased expression of CCR3 but not CCR10 could be detected during the induction of the CRA-induced pulmonary inflammation. To investigate the role of CCL28 in allergic airway responses, mice were treated with CCL28 antiserum 1 hour before receiving the final CRA challenge. The level of airway hyperresponsiveness in mice treated with anti-CCL28 was significantly reduced at 24 hours, but not 8 hours, compared to mice receiving control serum. This reduction was not related to decreased Th2 cytokine, chemokine, or leukotriene levels at 24 hours although peribronchial eosinophilia was significantly reduced. Thus, CCL28 appears to play a role in regulating eosinophil recruitment to peribronchial regions of the lung possibly by coordinated temporal production with eotaxin.

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“…20,21 In the mouse system, CCR3 expression is almost exclusively detected on eosinophils. 22,23 Importantly, recent studies have demonstrated that CCR3 disruption impaired eosin-ophil recruitment in acute models of experimental asthma. 24 -26 In addition to regulating eosinophil trafficking into mucosal tissues, the eotaxins activate the respiratory burst apparatus, induce degranulation, and up-regulate adhesion molecule expression.…”

mentioning

confidence: 99%

Eosinophils and CCR3 Regulate Interleukin-13 Transgene-Induced Pulmonary Remodeling

Fulkerson

Fischetti

Rothenberg

2006

The American Journal of Pathology

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Interleukin (IL)-13 transgene overexpression in the lung induces features of chronic inflammatory lung disorders, including an eosinophil-rich inflammatory cell infiltration, airway hyper-reactivity, and remodeling of the airway (eg, subepithelial fibrosis, goblet cell metaplasia, and smooth muscle hypertrophy and hyperplasia). Here, we aimed to define the role of eosinophils and eosinophil signaling molecules [eg, eotaxins and CC chemokine receptor (CCR) 3] in IL-13-mediated airway disease. To accomplish this, we mated IL-13-inducible lung transgenic mice with mice deficient in eosinophil chemoattractant molecules (eotaxin-1, eotaxin-2, and their receptor CCR3) and with mice genetically deficient in eosinophils (⌬dbl-GATA). We report that in the absence of eotaxin-2 or CCR3, there was a profound reduction in IL-13-induced eosinophil recruitment into the lung lumen. In contrast, in the absence of eotaxin-1, there was a fourfold increase in IL-13-mediated eosinophil recruitment into the airway. IL-13 transgenic mice deficient in CCR3 had a 98% reduction in lung eosinophils. Furthermore, the reduction in pulmonary eosinophils correlated with attenuation in IL-13-induced mucus cell metaplasia and collagen deposition. Mechanistic analysis identified alterations in pulmonary protease and transforming growth factor-␤ 1 expression in eosinophil-deficient mice. Taken together , these data definitively identify a functional contribution by eosinophils on the effects of chronic IL-13 expression in the lung. Asthma, one of the most common serious chronic diseases of childhood, is an inflammatory lung disease characterized by airway wall remodeling and reduced respiratory function. The chronic inflammatory process, with an airway infiltrate composed primarily of CD4 ϩ lymphocytes and eosinophils, contributes to airway remodeling, defined as altered lung structural changes.1 These structural changes in the airway include mucus cell metaplasia and increased deposition of collagen, proteoglycans, and other matrix proteins in the subepithelial layer.2 Importantly, these structural changes are implicated, at least partially, in the clinical manifestations of asthma.

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Ablation of eosinophils leads to a reduction of allergen-induced pulmonary pathology

Cited by 94 publications

References 36 publications

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Temporal Production of CCL28 Corresponds to Eosinophil Accumulation and Airway Hyperreactivity in Allergic Airway Inflammation

Eosinophils and CCR3 Regulate Interleukin-13 Transgene-Induced Pulmonary Remodeling

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