The Bateson Centre, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
J Immunol. 2019 Jan 15;202(2):494-502. doi: 10.4049/jimmunol.1801139. Epub 2018 Dec 14.
Drug-resistant mycobacteria are a rising problem worldwide. There is an urgent need to understand the immune response to tuberculosis to identify host targets that, if targeted therapeutically, could be used to tackle these currently untreatable infections. In this study we use an Il-1β fluorescent transgenic line to show that there is an early innate immune proinflammatory response to well-established zebrafish models of inflammation and infection. We demonstrate that host-derived hypoxia signaling, mediated by the Hif-1α transcription factor, can prime macrophages with increased levels of Il-1β in the absence of infection, upregulating neutrophil antimicrobial NO production, leading to greater protection against infection. Our data link Hif-1α to proinflammatory macrophage Il-1β transcription in vivo during early mycobacterial infection and importantly highlight a host protective mechanism, via antimicrobial NO, that decreases disease outcomes and that could be targeted therapeutically to stimulate the innate immune response to better deal with infections.
耐药性分枝杆菌是一个全球性的日益严重的问题。迫切需要了解对结核病的免疫反应，以确定宿主靶点，如果在治疗上针对这些靶点，可能用于解决这些目前无法治疗的感染。在这项研究中，我们使用 Il-1β 荧光转基因系来显示，在建立良好的炎症和感染的斑马鱼模型中，存在早期的固有免疫炎症反应。我们证明，由 Hif-1α 转录因子介导的宿主来源的低氧信号可以在没有感染的情况下使巨噬细胞预先产生高水平的 Il-1β，上调中性粒细胞抗菌性 NO 的产生，从而导致对感染的更大保护。我们的数据将 Hif-1α 与体内早期分枝杆菌感染期间的促炎巨噬细胞 Il-1β 转录联系起来，并重要地突出了一种宿主保护机制，通过抗菌性 NO，降低疾病结果，并且可以在治疗上靶向，以刺激先天免疫反应，更好地应对感染。
