The adaptor protein insulin receptor substrate 2inhibits alternative macrophage activation andallergic lung inflammation

摘要

Insulin receptor substrate 2 (IRS2) is an adaptor protein that becomes tyrosine-phosphorylated in responseto 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 inallergic disease, we evaluated the responses of IRS2-deficient (IRS2) mice. Unexpectedly, loss of IRS2resulted in a substantial increase in the expression of a subset of genes associated with the generationof alternatively activated macrophages (AAMs) in response to IL-4 or IL-13 in vitro. AAMs secrete factorsthat enhance allergic responses and promote airway remodeling. Moreover, compared to IRS2+/+ mice,IRS2+/- and IRS2-/- mice developed enhanced pulmonary inflammation, accumulated eosinophils andAAMs, and exhibited airway and vascular remodeling upon allergen stimulation, responses that partiallydepended onmacrophage-intrinsic IRS2 signaling. Both in unstimulated and IL-4–stimulatedmacrophages,lack of IRS2 enhanced phosphorylation of Akt and ribosomal S6 protein. Thus, we identified a critical inhibitoryloop downstreamof IRS2, demonstrating an unanticipated and previously unrecognized role for IRS2 insuppressing allergic lung inflammation and remodeling.