The cytokines IL-4 and IL-13 are produced by Type 2 (TH2) helper T cells in response to antigen receptor engagement, by mast cells and basophils upon cross-linkage of the high affinity receptor for immunoglobulin E (IgE), and by activated eosinophils. These two cytokines elicit similar responses in vitro, many of which are associated with allergy and asthma. These responses are elicited by binding to two types of high affinity receptor complexes (Type I and Type II) and initiating signal transduction pathways primarily dictated by the IL-4Ra chain. The regulation of TH2 development and mucus secretion by lung epithelial cells are key responses shown to be regulated by the IL-4Ra during allergic inflammation and are dependent upon STAT6 expression. In addition, we recently found that expression of the IL-4Ra on bone-marrow derived, non-lymphoid cells greatly enhances the eosinophilic inflammation in the lungs in an ovalbumin induced model of allergic inflammation. Preliminary phenotyping suggests a role for signaling by the IL-4Ra on MHC Class II+, CD11b+ mononuclear cells and on eosinophils. It is not known if these cells are primarily responding to IL-4 or IL-13. We have found a differential ability of IL-4 and IL-13 to induce the IRS2 signaling pathway that is recruited by a sequence motif in the IL-4Ra called the I4R-motif. Our broad goal of this application is to understand the molecular mechanisms of signaling through the IL-4Ra by IL-4 and IL-13 and its contribution to the pathogenesis of asthma. Based on our preliminary results, we propose that signaling by the Type I receptor preferentially activates the IRS2 signaling pathway, that signaling by the IL-4Ra expressed on macrophages and/or eosinophils substantially contributes to the severity of allergic inflammation, and that the critical signaling is mediated by IL-4 through the Type I receptor, rather than by IL-13.
The specific aims designed to test these hypotheses are 1) To characterize the differences in signaling responses between IL-4 and IL-13, 2) To elucidate differences in IL-4- and IL-13- induced biological responses in macrophages and eosinophils, and 3) To test the contribution of the IL-4Ra+ macrophages and eosinophils to the severity of allergic lung inflammation in vivo. Therapeutic strategies targeting the cytokines IL-4 and IL-13 or their receptors and signaling pathways are currently being developed to treat allergy and asthma. Our studies will provide a greater understanding of their mechanism of action and contribution to allergic inflammation. This new knowledge could help to develop better approaches to treat allergy and asthma.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Minnicozzi, Michael
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University of Maryland Baltimore
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Dasgupta, Preeta; Dorsey, Nicolas J; Li, Jiaqi et al. (2016) The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation. Sci Signal 9:ra63
Keegan, Achsah D; Shirey, Kari Ann; Bagdure, Dayanand et al. (2016) Enhanced allergic responsiveness after early childhood infection with respiratory viruses: Are long-lived alternatively activated macrophages the missing link? Pathog Dis 74:
Mogie, G; Shanks, K; Nkyimbeng-Takwi, E H et al. (2013) Neuroimmune semaphorin 4A as a drug and drug target for asthma. Int Immunopharmacol 17:568-75
Porter, Holly A; Perry, Anthony; Kingsley, Chris et al. (2013) IRS1 is highly expressed in localized breast tumors and regulates the sensitivity of breast cancer cells to chemotherapy, while IRS2 is highly expressed in invasive breast tumors. Cancer Lett 338:239-48
Yang, Zhonghan; Grinchuk, Viktoriya; Urban Jr, Joseph F et al. (2013) Macrophages as IL-25/IL-33-responsive cells play an important role in the induction of type 2 immunity. PLoS One 8:e59441
Rajaiah, Rajesh; Perkins, Darren J; Polumuri, Swamy Kumar et al. (2013) Dissociation of endotoxin tolerance and differentiation of alternatively activated macrophages. J Immunol 190:4763-72
Dasgupta, Preeta; Qi, Xiulan; Smith, Elizabeth P et al. (2013) Absence of the common gamma chain (?(c)), a critical component of the Type I IL-4 receptor, increases the severity of allergic lung inflammation. PLoS One 8:e71344
Dorsey, Nicolas J; Chapoval, Svetlana P; Smith, Elizabeth P et al. (2013) STAT6 controls the number of regulatory T cells in vivo, thereby regulating allergic lung inflammation. J Immunol 191:1517-28
Dasgupta, Preeta; Keegan, Achsah D (2012) Contribution of alternatively activated macrophages to allergic lung inflammation: a tale of mice and men. J Innate Immun 4:478-88
Luzina, Irina G; Keegan, Achsah D; Heller, Nicola M et al. (2012) Regulation of inflammation by interleukin-4: a review of ""alternatives"". J Leukoc Biol 92:753-64

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