STAT6-IP-dependent inhibition of type 2 innate and Th2 adaptive immunity in the murine lung.

Abstract

Type 2 airway inflammation is one of the main characteristics of allergen-induced asthma. Evidence from animal studies supports a model in which inhalation of allergens triggers epithelial cell release of alarmin cytokines, including IL-33, which activate a number of innate cells in the lung, including group 2 innate lymphoid cells (ILC2s), which produce large amounts of IL-13 and IL-5, to amplify allergic inflammation. Amongst other activities, ILC2-derived IL-13 promotes DC migration to the lung draining mediastinal lymph nodes (MLNs). Our published data indicate that topical administration of an immunomodulatory peptide, STAT6-IP, at the time of antigen priming inhibits T helper 2 adaptive immunity in murine models of asthma, at least in part, through inhibition of dendritic cells (DCs). In this study, we sought to clarify inhibitory activity of STAT6-IP toward DC responses in the lung and the lung draining MLNs induced by IL-33 and ovalbumin (OVA). Our data show that STAT6-IP reduced expansion of total and IL-13-producing ILC2s in OVA/IL-33-treated mice. STAT6-IP also inhibited OVA/IL-33-induced recruitment to and activation of lung DCs, which in turn reduced DC migration and CD4+ Th2 differentiation in the lung MLNs. When challenged several weeks later with OVA, allergic inflammatory responses, including airway hyperresponsiveness, were reduced in STAT6-IP-treated mice. STAT6-IP retained inhibitory activity whether delivered before or after OVA/IL-33 and activity coincided with expansion of IL-13-producing ILC2s. Altogether, our findings provide insight into mechanisms by which STAT6-IP interacts with innate immune cells of the lung to reduce maladaptive type 2 innate and T helper 2 adaptive immunity.