Insulin Receptor Substrate (IRS)2 is an adaptor that mediates anti-apoptotic signals in response to IL-4 or IL-13 in addition to regulating insulin signaling. Studies have shown that IRS2 plays a role in IL-4-induced proliferation of CD4+ T cells and secretion of TH2 cytokines in vitro. However, the functional significance of this pathway in induction of allergic lung inflammation has not been assessed. We previously demonstrated that IL-4 induced greater phosphorylation of IRS2 and expression of genes associated with the alternative activation of macrophages (AAM) when compared to IL-13, suggesting that IRS2 may be required for AAM differentiation. To examine the role of IRS2 in AAM gene induction and pulmonary inflammation, we utilized IRS-2-/- mice. Surprisingly, IRS2-/- mice developed enhanced pulmonary inflammation with significantly increased recruitment of eosinophils and macrophages in comparison to IRS2+/+ mice. Additionally, greater numbers of FIZZ1, YM1 and Arginase1 transcripts were detected in response to IL-4 or IL-13 in macrophages lacking IRS2 in vitro. This also correlated to increased YM1 protein expression in macrophages in vivo in the allergic airways in IRS2-/- mice. Interestingly, IRS2+/- mice demonstrated a gene dosage effect; they developed intermediate levels of inflammation, cellular infiltration and AAM gene/protein expression. Thus, this study identifies a previously unrecognized role for the IRS2 pathway in suppressing asthma responses.
- Copyright © 2013 by The American Association of Immunologists, Inc.