Fanny Manoussa, Nascimento Mégane, Baron Ludivine, Schricke Corinne, Maillet Isabelle, Akbal Myriam, Riteau Nicolas, Le Bert Marc, Quesniaux Valérie, Ryffel Bernhard, Gombault Aurélie, Même Sandra, Même William, Couillin Isabelle
University of Orleans and CNRS, UMR7355, Orleans, France.
University of Orleans and CNRS, UPR4301, Orleans, France.
Front Immunol. 2018 Jun 25;9:1476. doi: 10.3389/fimmu.2018.01476. eCollection 2018.
Idiopathic pulmonary fibrosis is a progressive, devastating, and yet untreatable fibrotic disease of unknown origin. Interleukin-33 (IL-33), an IL-1 family member acts as an alarmin with pro-inflammatory properties when released after stress or cell death. Here, we investigated the role of IL-33 in the bleomycin (BLM)-induced inflammation and fibrosis model using mice IL-33 receptor [chain suppression of tumorigenicity 2 (ST2)] mice compared with C57BL/6 wild-type mice. Unexpectedly, 24 h post-BLM treatment ST2-deficient mice displayed augmented inflammatory cell recruitment, in particular by neutrophils, together with enhanced levels of chemokines and remodeling factors in the bronchoalveolar space and/or the lungs. At 11 days, lung remodeling and fibrosis were decreased with reduced M2 macrophages in the lung associated with M2-like cytokine profile in ST2-deficient mice, while lung cellular inflammation was decreased but with fluid retention (edema) increased. magnetic resonance imaging (MRI) analysis demonstrates a rapid development of edema detectable at day 7, which was increased in the absence of ST2. Our results demonstrate that acute neutrophilic pulmonary inflammation leads to the development of an IL-33/ST2-dependent lung fibrosis associated with the production of M2-like polarization. In addition, non-invasive MRI revealed enhanced inflammation with lung edema during the development of pulmonary inflammation and fibrosis in absence of ST2.
特发性肺纤维化是一种病因不明的进行性、毁灭性且无法治疗的纤维化疾病。白细胞介素-33（IL-33）是白细胞介素-1家族成员，在应激或细胞死亡后释放时作为具有促炎特性的警报素。在此，我们使用小鼠白细胞介素-33受体[肿瘤抑制性2链（ST2）]小鼠与C57BL/6野生型小鼠比较，研究了IL-33在博来霉素（BLM）诱导的炎症和纤维化模型中的作用。出乎意料的是，在BLM治疗后24小时，ST2缺陷小鼠显示出炎症细胞募集增加，尤其是中性粒细胞，同时支气管肺泡腔和/或肺中的趋化因子和重塑因子水平升高。在第11天，肺重塑和纤维化减少，肺中M2巨噬细胞减少，与ST2缺陷小鼠中的M2样细胞因子谱相关，而肺细胞炎症减少，但液体潴留（水肿）增加。磁共振成像（MRI）分析表明，在第7天可检测到水肿迅速发展，在没有ST2的情况下水肿增加。我们的结果表明，急性中性粒细胞性肺部炎症导致与M2样极化产生相关的IL-33/ST2依赖性肺纤维化的发展。此外，非侵入性MRI显示，在没有ST2的情况下，肺部炎症和纤维化发展过程中炎症增强并伴有肺水肿。
