STAT6-IP–Dependent Disruption of IL-33–Mediated ILC2 Expansion and Type 2 Innate Immunity in the Murine Lung

Abstract

Abstract Recent interest has focused on innate-type cytokines as promoters of type 2 immunity and targets for drug development in asthma. IL-33 induces production of IL-4 and/or IL-13, which is associated with STAT6-dependent responses in innate cells, including group 2 innate lymphoid cells (ILC2s), macrophages, and eosinophils. Our published data show that STAT6-immunomodulatory peptide (STAT6-IP), an immunomodulatory peptide designed to inhibit the STAT6 transcription factor, reduces induction of Th2 adaptive immunity in respiratory syncytial virus infection and asthma models. Nevertheless, the mechanism of STAT6-IP–dependent inhibition has remained obscure. In this study, we demonstrate that STAT6-IP reduced IL-33–induced type 2 innate lung inflammation. Specifically, our data show that STAT6-IP reduced recruitment and activation of eosinophils as well as polarization of alternatively activated macrophages. Decreases in these cells correlated with reduced levels of IL-5 and IL-13 as well as several type 2 chemokines in the bronchoalveolar lavage fluid. STAT6-IP effectively inhibited expansion of ILC2s as well as the number of IL-5– and IL-13–producing ILC2s. Our data suggest that STAT6-IP effectively disrupts IL-13–dependent positive feedback loops, initiated by ILC2 activation, to suppress IL-33–induced type 2 innate immunity in the murine lung.