The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness

Abstract

CCR3 is a chemokine receptor initially thought specific to eosinophils but subsequently identified on TH2 cell subsets, basophils, mast cells, neural tissue, and some epithelia. Because of the prominent role of these cells in allergic disease, including asthma, we generated mice deficient in CCR3 to determine its contribution in a model of allergic airway disease. Here we show that CCR3 is important for the basal trafficking of eosinophils to the intestinal mucosa but not the lung. In contrast, CCR3 disruption significantly curtails eosinophil recruitment to the lung after allergen challenge, with the majority of the eosinophils being arrested in the subendothelial space. Further, a role for CCR3 in mast cell homing has been identified; after sensitization and allergen challenge, we find increased numbers of intraepithelial mast cells in the trachea of knockout mice. Physiologically, we find that the net result of these complex cell fates after sensitization and allergen challenge is a paradoxical increase in airway responsiveness to cholinergic stimulation. These data underscore a more complex role for CCR3 in allergic disease than was anticipated.

Granulocyte-Macrophage Colony-Stimulating Factor Is Required for Bronchial Eosinophilia in a Murine Model of Allergic Airway Inflammation

“…CCR3 is an important chemokine receptor on eosinophils, as mice lacking functional CCR3 genes show impaired eosinophil recruitment to the lungs in a model of allergic airway inflammation (22). Therefore, changes to CCR3 or its ligands could explain the lack of infiltration of eosinophils in the airways of GM-CSF Ϫ/Ϫ mice.…”

Iddm30 Controls Pancreatic Expression of Ccl11 (Eotaxin) and the Th1/Th2 Balance within the Insulitic Lesions

“…Given the genomic location of Ccl24 and Ccl26 and the evidence that the regulation of their expression is coordinated with that of Ccl11 in allergic and other Th2-mediated immune responses (32,34,45), we sequenced the coding regions of these two genes and assessed their transcript levels in the pancreas of BBDP and ACI.1u.lyp parental strains. Of note, Ccl11 itself is located on chromosome 10, and it was therefore plausible that a chromosome 12 genetic polymorphism in our cross would differentially regulate the expression of Ccl11 in trans and that of the two other eotaxins in cis.…”

“…The critical role of Ccl11 in driving the recruitment of Ccr3-expressing Th2 lymphocytes, mast cells, and eosinophils to the site of atopic and other Th2-mediated immune responses is well characterized (32,34,45,51). Through this recruitment and the cytokines released by the attracted cells, Ccl11 contributes to the skewing of Th differentiation away from Th1 to Th2 (34).…”

“…Increased expression of Ccl11 typically contributes to the recruitment of Th2 cells that express Ccr3, the chemokine receptor for Ccl11, to the site of inflammation (28,32,34,45). The observation that high levels of pancreatic Ccl11 transcripts are associated with resistance to T1D in BBDP rats led us to determine whether these high levels are also correlated with a Th2 bias in the insulitic lesion of these animals.…”

“…The physiological significance of this expression remains elusive, although it has been shown that the interaction of extracellular matrix proteins with b cells results in NF-kB activation and the subsequent synthesis of cytokines by b cells, in vitro (27). Ccl11 is one of the three members of the eotaxin family of C-C chemokines that are potent chemoattractants for Ccr3-expressing cells, which include eosinophils, mast cells, basophils, neutrophils, and Th2 lymphocytes (28)(29)(30)(31)(32)(33)(34). Although the presence of eosinophils and mast cells within the insulitic lesions of BBDP rats has been previously reported (35)(36)(37), the observation that Ccl11 is upregulated in the target organ of this diabetogenic process remains puzzling (24,37), particularly because diabetes in the BBDP rat is a Th1-mediated autoimmune disease (38)(39)(40).…”