皮质类固醇通过阻断线粒体膜通透性转换来抑制结核分枝杆菌诱导的宿主细胞坏死。

Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition.

机构信息

Department I of Internal Medicine, University of Cologne, 50937, Cologne, Germany.

Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.

出版信息

Nat Commun. 2019 Feb 8;10(1):688. doi: 10.1038/s41467-019-08405-9.

Corticosteroids are host-directed drugs with proven beneficial effect on survival of tuberculosis (TB) patients, but their precise mechanisms of action in this disease remain largely unknown. Here we show that corticosteroids such as dexamethasone inhibit necrotic cell death of cells infected with Mycobacterium tuberculosis (Mtb) by facilitating mitogen-activated protein kinase phosphatase 1 (MKP-1)-dependent dephosphorylation of p38 MAPK. Characterization of infected mixed lineage kinase domain-like (MLKL) and tumor necrosis factor receptor 1 (TNFR1) knockout cells show that the underlying mechanism is independent from TNFα-signaling and necroptosis. Our results link corticosteroid function and p38 MAPK inhibition to abrogation of necrotic cell death mediated by mitochondrial membrane permeability transition, and open new avenues for research on novel host-directed therapies (HDT).

皮质类固醇是一种宿主导向药物，已被证明对结核病（TB）患者的生存有益，但它们在这种疾病中的确切作用机制在很大程度上仍不清楚。在这里，我们表明，皮质类固醇如地塞米松通过促进有丝分裂原激活的蛋白激酶磷酸酶 1（MKP-1）依赖性 p38 MAPK 去磷酸化，抑制结核分枝杆菌（Mtb）感染细胞的坏死性细胞死亡。对感染的混合谱系激酶结构域样（MLKL）和肿瘤坏死因子受体 1（TNFR1）敲除细胞的特征分析表明，其潜在机制独立于 TNFα 信号和坏死性细胞死亡。我们的研究结果将皮质类固醇的功能和 p38 MAPK 抑制与线粒体膜通透性转换介导的坏死性细胞死亡的阻断联系起来，并为新的宿主导向治疗（HDT）的研究开辟了新的途径。