TY - JOUR
T1 - The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation
AU - Dasgupta, Preeta
AU - Dorsey, Nicolas J.
AU - Li, Jiaqi
AU - Qi, Xiulan
AU - Smith, Elizabeth P.
AU - Yamaji-Kegan, Kazuyo
AU - Keegan, Achsah D.
N1 - Funding Information:
This work was supported by U.S. Public Health Service (PHS) grants AI038985 and HL110111 and VA-MERIT I01 BX001850 to A.D.K., a Pulmonary Hypertension Association/American Thoracic Society/Pfizer Research Fellowship in Pulmonary Arterial Hypertension to K.Y.-K., and PHS grants T32HL06798 and T32AI007540 and a United Negro College Fund/Merck Science Initiative to N.J.D.
Publisher Copyright:
© 2016, American Association for the Advancement of Science. All rights reserved.
PY - 2016/6/21
Y1 - 2016/6/21
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.aad6724
DO - 10.1126/scisignal.aad6724
M3 - Article
C2 - 27330190
AN - SCOPUS:84975824315
SN - 1945-0877
VL - 9
JO - Science signaling
JF - Science signaling
IS - 433
M1 - ra63
ER -