Expression of IL-5 receptor alpha by murine and human lung neutrophils.

The role of eosinophilia in atopic diseases, including asthma, is well established, as is the well-known role of IL-5 as a major eosinophilopoeitin and chemoattractant. Following influenza A virus infection of mice, type 2 innate lymphoid cells are recruited to the respiratory tract and produce large quantities of IL-5, which contributes to the recruitment of eosinophils into the infected lungs during the recovery phase of infection. We demonstrate here that while IL-5 is required for optimal recovery from influenza A virus infection in BALB/c and C57BL/6 mice, the protective effect of IL-5 is independent of eosinophils, suggesting an alternative cellular target. We describe the unexpected finding of IL-5 receptor alpha (CD125) expression on neutrophils infiltrating the inflamed mouse lungs, as well as on neutrophils at other anatomic sites. We extend this finding of neutrophil CD125 expression to humans, specifically to neutrophils found in the bronchoalveolar lavage fluid from the inflamed lungs of children with treatment-refractory asthma. We further demonstrate that the IL-5 receptor on neutrophils is capable of signal transduction. Our data provide further evidence that neutrophils can play a role bridging atopic type 2 and innate anti-microbial immunity.

Conformational epitopes at cadherin calcium-binding sites and p120-catenin phosphorylation regulate cell adhesion.

We investigated changes in cadherin structure at the cell surface that regulate its adhesive activity. Colo 205 cells are nonadhesive cells with a full but inactive complement of E-cadherin-catenin complexes at the cell surface, but they can be triggered to adhere and form monolayers. We were able to distinguish the inactive and active states of E-cadherin at the cell surface by using a special set of monoclonal antibodies (mAbs). Another set of mAbs binds E-cadherin and strongly activates adhesion. In other epithelial cell types these activating mAbs inhibit growth factor-induced down-regulation of adhesion and epithelial morphogenesis, indicating that these phenomena are also controlled by E-cadherin activity at the cell surface. Both types of mAbs recognize conformational epitopes at different interfaces between extracellular cadherin repeat domains (ECs), especially near calcium-binding sites. Activation also induces p120-catenin dephosphorylation, as well as changes in the cadherin cytoplasmic domain. Moreover, phospho-site mutations indicate that dephosphorylation of specific Ser/Thr residues in the N-terminal domain of p120-catenin mediate adhesion activation. Thus physiological regulation of the adhesive state of E-cadherin involves physical and/or conformational changes in the EC interface regions of the ectodomain at the cell surface that are mediated by catenin-associated changes across the membrane.