New data support a downregulatory role for the alternate IL-13 receptor

Abstract

IL-13 has been shown to have a critical role in asthma and allergic diseases, but the way in which this cytokine signals has not been fully elucidated. There are at least 2 distinct receptor signaling components: the IL-4 receptor (R) α and IL-13R α-1 molecules, both of which mediate the action of IL-13. In addition, there is a high-affinity receptor, IL-13R α-2, which exists in both transmembrane and soluble forms. To address the role of this nonsignaling IL-13 receptor, the investigators generated IL-13R α-2 gene knockout (KO) mice. These mice did not have any obvious abnormalities in STAT6 signaling. However, there was a marked dysregulation of the IL-13 distribution and immunoglobulin production. In particular, the KO animals had nearly undetectable levels of serum IL-13 but modest increases in tissue levels of this cytokine. In addition, there were increased serum levels of a variety of immunoglobulins, including IgE, IgA, Ig2a, and Ig2b, in the KO animals. In consistency with an inhibitory role for this receptor, the KO mice contained increased macrophage progenitor cells; in addition, KO macrophages release decreased levels of nitric oxide and IL-12. To further characterize the role of this receptor in a disease state, the investigators examined the consequences of the gene deletion on experimental infection with the parasitic helminth Schistosoma mansoni. The investigators first demonstrated that IL-13R α-2 expression was induced after the onset of tissue fibrosis in an IL-10–, IL-13–, and STAT6-dependent fashion. Notably, the Schistosoma-infected KO mice showed a marked exacerbation in liver fibrosis, even though there was no change in tissue eosinophilia or mastocytosis. Fibrosis was not associated with increased production of TH2-associated cytokines. Importantly, fibrotic pathology was reversed when the IL-13R α-2 KO mice were treated with a soluble IL-13R α-2-Fc construct. These studies thus demonstrate a central role for IL-13R α-2 in the downregulation of chronic TH2-associated immune responses. Collectively, the studies reinforce the view that IL-13 signaling is attenuated by IL-13R α-2, which therefore serves as a “decoy receptor.”