title: The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation.
abstract: Insulin receptor substrate 2 (IRS2) is an adaptor protein that becomes tyrosine-phosphorylated in response to the cytokines interleukin-4 (IL-4) and IL-13, which results in activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. IL-4 and IL-13 contribute to allergic lung inflammation. To examine the role of IRS2 in allergic disease, we evaluated the responses of IRS2-deficient (IRS2(-/-)) mice. Unexpectedly, loss of IRS2 resulted in a substantial increase in the expression of a subset of genes associated with the generation of alternatively activated macrophages (AAMs) in response to IL-4 or IL-13 in vitro. AAMs secrete factors that enhance allergic responses and promote airway remodeling. Moreover, compared to IRS2(+/+) mice, IRS2(+/-) and IRS2(-/-) mice developed enhanced pulmonary inflammation, accumulated eosinophils and AAMs, and exhibited airway and vascular remodeling upon allergen stimulation, responses that partially depended on macrophage-intrinsic IRS2 signaling. Both in unstimulated and IL-4-stimulated macrophages, lack of IRS2 enhanced phosphorylation of Akt and ribosomal S6 protein. Thus, we identified a critical inhibitory loop downstream of IRS2, demonstrating an unanticipated and previously unrecognized role for IRS2 in suppressing allergic lung inflammation and remodeling.
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street Baltimore, MD 21201, USA. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Preeta
authors.initials: P
authors.lastname: Dasgupta
authors.affiliation: Medical Scientist Training Program, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Dorsey
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street Baltimore, MD 21201, USA.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street Baltimore, MD 21201, USA.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Qi
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street Baltimore, MD 21201, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Smith
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamaji-Kegan
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street Baltimore, MD 21201, USA. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Research and Development Service, U.S. Department of Veterans Affairs, Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA. akeegan@som.umaryland.edu.
authors.forename: Achsah D
authors.initials: AD
authors.lastname: Keegan
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt