National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
Sci Immunol. 2020 Oct 23;5(52). doi: 10.1126/sciimmunol.abc1884.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression () is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.
特发性肺纤维化（IPF）是一种致命的肺部疾病，其中气道巨噬细胞（AMs）发挥着关键作用。衣康酸已成为巨噬细胞功能的介质，但它在纤维化过程中的作用尚不清楚。在这里，我们揭示了衣康酸是肺部内源性抗纤维化因子。与对照组相比，IPF 患者支气管肺泡灌洗液中的衣康酸水平降低，并且 AM 中合成衣康酸的顺乌头酸脱羧酶表达（）降低。在博来霉素诱导的肺纤维化小鼠模型中，与野生型（WT）同窝仔鼠相比， 小鼠持续发生纤维化。与 WT 相比，组织驻留 AM 中的促纤维化基因表达增加，并且 WT 募集的单核细胞来源的 AM 过继转移可挽救小鼠免于发病表型。用衣康酸培养肺成纤维细胞可降低增殖和伤口愈合能力，并且体内吸入衣康酸可保护小鼠。总的来说，这些数据表明衣康酸对于控制肺部纤维化的严重程度至关重要，靶向该途径可能是一种可行的治疗策略。
