IL-22 Binding Protein Controls IL-22–Driven Bleomycin-Induced Lung Injury

Abstract

The high mortality rates of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) challenge the field to identify biomarkers and factors that can be exploited for therapeutic approaches. IL-22 is a cytokine that has antibacterial and reparative properties in the lung. However, it can also exacerbate inflammation and requires tight control by the extracellular inhibitory protein known as IL-22 binding protein (IL-22BP) (Il22ra2). Here we demonstrate the necessity of IL-22BP in controlling and preventing acute lung injury using IL-22BP knockout mice (Il22ra2-/-) in the bleomycin model of ALI/ARDS. Il22ra2-/- mice had greater sensitivity (weight loss and death) and pulmonary inflammation in the acute phase (first 7 days) of the injury compared to wild type C57Bl/6 controls. The inflammation was driven by excess IL-22 production, inducing the influx of pathogenic IL-17A+ γδT cells to the lung. Interestingly, this inflammation is initiated in part, by the non-canonical IL-22 signaling to macrophages, which express the IL-22 receptor (Il22ra1) in vivo after bleomycin challenge. We further show that these IL-22Ra1+ macrophages can be stimulated by IL-22 to produce a number of IL-17 inducing cytokines such as IL-1β, IL-6 and TGF-β1. Together, our results suggest that IL-22BP prevents IL-22 signaling to macrophages and reduces bleomycin-mediated lung injury.