Research ArticleImmunology

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

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Sci. Signal.  21 Jun 2016:
Vol. 9, Issue 433, pp. ra63
DOI: 10.1126/scisignal.aad6724

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Limiting lung inflammation

The adaptor protein IRS2 is recruited to receptors for the cytokines interleukin-4 (IL-4) and IL-13, where it becomes phosphorylated and activates downstream signaling. Because IL-4 and IL-13 cause allergic inflammation in the lung, strategies that block their signaling may prove therapeutic. Unexpectedly, when Dasgupta et al. knocked out IRS2 in mice, they found that IL-4 and IL-13 signaling and associated gene expression were increased rather than inhibited. The lungs of these mice had increased numbers of alternatively activated macrophages, which secrete factors that enhance allergic responses and promote airway remodeling. The IRS2-deficient mice had enhanced airway inflammation in response to allergen, which was associated with increased PI3K and Akt signaling in macrophages. Together, these results suggest that IRS2 mediates feedback inhibition of IL-4 and IL-13 signaling to limit allergic inflammation in the lung.

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.

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