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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.

journal_name

Sci Signal

journal_title

Science signaling

authors

Dasgupta P,Dorsey NJ,Li J,Qi X,Smith EP,Yamaji-Kegan K,Keegan AD

doi

10.1126/scisignal.aad6724

subject

Has Abstract

pub_date

2016-06-21 00:00:00

pages

ra63

issue

433

eissn

1945-0877

issn

1937-9145

pii

9/433/ra63

journal_volume

9

pub_type

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