Anti-ST2 antibody reduces airway hyperresponsiveness mediated by monocyte-derived macrophages during influenza A infection.

Abstract

Influenza A virus (IAV) infections trigger asthma attacks and cause airway hyperresponsiveness (AHR) in murine models. However, the mechanism by which AHR is induced remains to be fully elucidated. Here, we show that targeting the interleukin (IL)-33 suppression of tumorigenicity 2 (ST2) receptor complex with an anti-ST2 antibody during acute IAV infection of C57BL/6 mice reduced AHR, without affecting expansion of ILC2s and independently of IL-13. Among the lung inflammatory cells, the anti-ST2 antibody selectively reduced the monocyte-derived macrophages (MMs). Furthermore, AHR was reduced in C-C chemokine receptor 2 (CCR2)-knockout mice that have deficient MM recruitment. Depletion of MMs achieved by anti-Ly6C antibody administration also reduced AHR. The treatment of airway smooth muscle (ASM) with conditioned medium from IL-33-treated human THP-1-derived macrophages enhanced potassium chloride-induced ASM contraction. These findings suggest that MMs contribute to acute AHR following IAV infection in an IL-33-dependent manner, but independent of the ILC2/IL-13 axis. Additionally, IL-33 stimulates the release of macrophage-derived mediators that enhance airway smooth muscle contraction, offering a potential mechanistic basis for IAV-induced AHR.