An Alternate STAT 6-Independent Pathway Promotes Eosinophil Influx into Blood during Allergic Airway Inflammation

Background: Enhanced eosinophil responses have critical roles in the development of allergic diseases. IL-5 regulates the maturation, migration and survival of eosinophils, and IL-5 and eotaxins mediate the trafficking and activation of eosinophils in inflamed tissues. CD4 Th2 cells are the main producers of IL-5 and other cells such as NK also release this cytokine. Although multiple signalling pathways may be involved, STAT6 critically regulates the differentiation and cytokine production of Th2 cells and the expression of eotaxins. Nevertheless, the mechanisms that mediate different parts of the eosinophilic inflammatory process in different tissues in allergic airway diseases remain unclear. Furthermore, the mechanisms at play may vary depending on the context of inflammation and microenvironment of the involved tissues. Methodology/Principal Findings: We employed a model of allergic airway disease in wild type and STAT6-deficient mice to explore the roles of STAT6 and IL-5 in the development of eosinophilic inflammation in this context. Quantitative PCR and ELISA were used to examine IL-5, eotaxins levels in serum and lungs. Eosinophils in lung, peripheral blood and bone marrow were characterized by morphological properties. CD4 T cell and NK cells were identified by flow cytometry. Antibodies were used to deplete CD4 and NK cells. We showed that STAT6 is indispensible for eosinophilic lung inflammation and the induction of eotaxin-1 and -2 during allergic airway inflammation. In the absence of these chemokines eosinophils are not attracted into lung and accumulate in peripheral blood. We also demonstrate the existence of an alternate STAT6independent pathway of IL-5 production by CD4 and NK cells that mediates the development of eosinophils in bone marrow and their subsequent movement into the circulation. Conclusions: These results suggest that different points of eosinophilic inflammatory processes in allergic airway disease may be differentially regulated by the activation of STAT6-dependent and -independent pathways. Citation: Wang W, Hansbro PM, Foster PS, Yang M (2011) An Alternate STAT6-Independent Pathway Promotes Eosinophil Influx into Blood during Allergic Airway Inflammation. PLoS ONE 6(3): e17766. doi:10.1371/journal.pone. 0017766 Editor: Karen Mossman, McMaster University, Canada Received October 5, 2010; Accepted February 14, 2011; Published March 15, 2011 Copyright: 2011 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by project grants from the National Health & Medical Research Council of Australia (P. S. Foster and M. Yang) and the Cooperative Research Centre for Asthma and Airways (P. S. Foster and M. Yang). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: Ming.Yang@newcastle.edu. au (MY); Paul.Foster@newcastle.edu. au (PSF)