Key words: interleukin(IL)-4/IL-13 signaling, allergic inflammation, asthma, IRS-2, STAT6, alternatively activated macrophage.
We are interested in the basic mechanisms of signaling from the biology of the IL-4/IL-13 receptor, signal transduction and its regulation to the role of alternatively-activated macrophages (AAM) in the pathogenesis of allergic inflammation. IL-4 and/or IL-13 are critical for AAM differentiation from resting macrophages. AAM mediate Th2-type inflammatory responses (to allergens or helminths) and wound healing responses. AAM are considered “anti-inflammatory” and suppress inflammation by promoting fibrosis through release of chitinase-like molecules and matrix remodeling enzymes, inducing Tregs, dampening T-cell responses and producing anti-inflammatory cytokines. However, when AAM responses become chronic or are dysregulated, pathogenesis can result, as seen in lung fibrosis and tissue remodeling in asthma. The balance between AAM and classical inflammatory macrophages regulates the pathology of many diseases including obesity, cardiovascular disease and cancer. New projects include elucidating the molecular links between asthma and obesity and how gender and race affect asthma and obesity in humans.
Profile: Publications and Interests
Heller, N.M., Qi, X., Gesbert, F., Keegan, A.D. The extracellular and transmembrane domains of the γc and IL-13Rα1 chains, not their cytoplasmic domains, dictate the nature of signaling responses to IL-4 and IL-13. J Biol Chem. 2012 Jul 24.
Heller, N.M., Gwinn, W.M., Donnelly, R.P., Constant, S.L., Keegan, A.D. IL-4 Engagement of the Type I IL-4 Receptor Complex Enhances Mouse Eosinophil Migration to Eotaxin-1 In Vitro. PLoS One. 2012;7(6):e39673. Epub 2012 Jun 28.
Ford, A.Q., Heller, N.M., Stephenson, L., Boothby, M.R., Keegan A.D. An atopy-associated polymorphism in the ectodomain of the IL-4R(alpha) chain (V50) regulates the persistence of STAT6 phosphorylation. J Immunol. 2009 Aug 1;183(3): 1607-16.
• This paper was highlighted for its clinical relevance on MDLinx.com (Allergy/Immunology section).
Heller N.M., Qi X., Junttila I.S., Shirey K.A., Vogel S.N., Paul W.E., Keegan A.D. Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages. Sci Signaling. 2008 Dec 23, 1(51): ra17.
• This paper was the subject of a Perspective Review in the same issue:
Wills-Karp, M., and Finkelman, F. D. Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Signal. 2008, 1: pe55.
• and a Highlight in the JACI:
Rothenberg, M. E., and Nelson, H. S. News Beyond Our Pages. Journal of Allergy and Clinical Immunology. 2009, 123: 517.
LaPorte, S.L., Juo, Z.S., Vaclavikova, J., Colf, L.A., Qi, X., Heller, N.M., Keegan, A.D., Garcia, K.C. Molecular and Structural Basis of Cytokine Receptor Pleiotropy in the Interleukin-4/13 System. Cell, 2008 Jan 25; 132: 259-272.
• This paper was the basis of the Cover art and a Review in that issue:
Zdanov, A., and Wlodawer, A. A new look at cytokine signaling. Cell. 2008, 132: 179.
• and a Research Highlight in Nature Reviews Immunology:
Minton, K. Allergy and Asthma: What 'drives' IL-4 versus IL-13 signalling? Nat Rev Immunol. 2008, 8: 166.
Heller, N.M., Matsukura, S., Georas, S.N., Boothby, M.R., Stellato, C., Schleimer, R.P. Assessment of STAT6 as a Target of Glucocorticoid Action In Human Airway Epithelial Cells. Clin Exp Allergy. 2004 Nov; 34(11): 1690-700.
Heller, N.M., Matsukura, S., Georas, S.N., Boothby, M.R., Rothman, P.B., Stellato, C., Schleimer, R.P. Interferon-γ inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. Am J Respir Cell Mol Biol. 2004 Nov; 31(5): 573-82.
Fan J, Heller, N.M., Gorospe, M., Atasoy, U., Stellato, C. The role of post-transcriptional regulation in chemokine gene expression in inflammation and allergy. Eur Respir J. 2005 Nov; 26(5): 933-47.