Itaconate controls the severity of pulmonary fibrosis
Itaconate controls the severity of pulmonary fibrosis
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DOI：
10.1126/sciimmunol.abc1884
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发表时间：
2020-10-01
影响因子：
24.8
通讯作者：
Byrne, Adam J.
中科院分区：
文献类型：
--
作者：
Ogger, Patricia P.;Albers, Gesa J.;Byrne, Adam J.
特发性肺纤维化（IPF）是一种致命的肺部疾病，气道巨噬细胞（AM）在其中起着关键作用。衣康酸已成为巨噬细胞功能的介质，但其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一种内源性抗肺纤维化因子。与对照组相比，IPF患者AM支气管肺泡灌洗中衣康酸水平降低，衣康酸合成顺式乌头酸脱羧酶（ACOD 1）表达降低。在肺纤维化的博莱霉素鼠模型中，Acod 1（-/-）小鼠发生持续性纤维化，与野生型（WT）同窝仔不同。与WT相比，Acod 1（-/-）组织驻留AM中促纤维化基因表达增加，WT单核细胞募集AM的过继转移挽救了疾病表型小鼠。用衣康酸盐培养的肺成纤维细胞的增殖和伤口愈合能力降低，吸入衣康酸盐在小鼠体内具有保护作用。总的来说，这些数据确定衣康酸盐对于控制肺纤维化的严重程度至关重要，并且靶向该途径可能是一种可行的治疗策略。
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 (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1(-/-) imice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1(-/-) 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.