biostudies-literatureZhang ZNHLBI NIH HHSNational Institutes of Health338-352https://www.ebi.ac.uk/biostudies/studies/S-EPMC10913761biostudies-literatureUnknown194(3)The high mortality rates of acute lung injury and acute respiratory distress syndrome 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 also can exacerbate inflammation and requires tight control by the extracellular inhibitory protein known as IL-22 binding protein (IL-22BP) (Il22ra2). This study showed the necessity of IL-22BP in controlling and preventing acute lung injury using IL-22BP knockout mice (Il22ra2^-/-) in the bleomycin model of acute lung injury/acute respiratory distress syndrome. Il22ra2^-/- mice had greater sensitivity (weight loss and death) and pulmonary inflammation in the acute phase (first 7 days) of the injury compared with wild-type C57Bl/6 controls. The inflammation was driven by excess IL-22 production, inducing the influx of pathogenic IL-17A⁺ γδ T cells to the lung. Interestingly, this inflammation was initiated in part by the noncanonical IL-22 signaling to macrophages, which express the IL-22 receptor (Il22ra1) in vivo after bleomycin challenge. This study further showed that IL-22 receptor alpha-1⁺ macrophages can be stimulated by IL-22 to produce a number of IL-17-inducing cytokines such as IL-1β, IL-6, and transforming growth factor-β1. Together, the results suggest that IL-22BP prevents IL-22 signaling to macrophages and reduces bleomycin-mediated lung injury.The American journal of pathologyIL-22 Binding Protein Controls IL-22-Driven Bleomycin-Induced Lung Injury.PMC10913761RO1HL122760R01 HL122760Jones MFrydman JAGaleas-Pena MZhang ZAllen MJChakawa MBPociask DfalseIL-22 Binding Protein Controls IL-22-Driven Bleomycin-Induced Lung Injury.The high mortality rates of acute lung injury and acute respiratory distress syndrome 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 also can exacerbate inflammation and requires tight control by the extracellular inhibitory protein known as IL-22 binding protein (IL-22BP) (Il22ra2). This study showed the necessity of IL-22BP in controlling and preventing acute lung injury using IL-22BP knockout mice (Il22ra2^-/-) in the bleomycin model of acute lung injury/acute respiratory distress syndrome. Il22ra2^-/- mice had greater sensitivity (weight loss and death) and pulmonary inflammation in the acute phase (first 7 days) of the injury compared with wild-type C57Bl/6 controls. The inflammation was driven by excess IL-22 production, inducing the influx of pathogenic IL-17A⁺ γδ T cells to the lung. Interestingly, this inflammation was initiated in part by the noncanonical IL-22 signaling to macrophages, which express the IL-22 receptor (Il22ra1) in vivo after bleomycin challenge. This study further showed that IL-22 receptor alpha-1⁺ macrophages can be stimulated by IL-22 to produce a number of IL-17-inducing cytokines such as IL-1β, IL-6, and transforming growth factor-β1. Together, the results suggest that IL-22BP prevents IL-22 signaling to macrophages and reduces bleomycin-mediated lung injury.2024-01-01T00:00:00Z2024 Mar2025-04-03T23:36:22.477Z2025-04-03T23:36:22.477ZS-EPMC109137613810156710.1016/j.ajpath.2023.11.011