Type I Interferons Are Involved in the Intracellular Growth Control of Mycobacterium abscessus by Mediating NOD2-Induced Production of Nitric Oxide in Macrophages.
Type I Interferons Are Involved in the Intracellular Growth Control of Mycobacterium abscessus by Mediating NOD2-Induced Production of Nitric Oxide in Macrophages.
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DOI：
10.3389/fimmu.2021.738070
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发表时间：
2021
影响因子：
7.3
通讯作者：
Park JH
中科院分区：
文献类型：
--
作者：
Ahn JH;Park JY;Kim DY;Lee TS;Jung DH;Kim YJ;Lee YJ;Lee YJ;Seo IS;Song EJ;Jang AR;Yang SJ;Shin SJ;Park JH
结核分枝杆菌（Mycobacterium dumbersessus，MAB）是一种生长迅速、耐多药的非结核分枝杆菌，可引起包括肺部疾病在内的多种疾病。虽然已经知道I型干扰素（IFN）有助于宿主防御细菌感染，但I型IFN对抗MAB感染的作用仍不清楚。在本研究中，我们表明，rIFN-β治疗减少了MAB在巨噬细胞的细胞内生长。IFN-α/β受体（IFNAR）缺陷导致MAB感染的巨噬细胞中一氧化氮（NO）产生减少。一致地，rIFN-β处理增强了MAB响应的iNOS基因和蛋白的表达以及NO的产生。我们还发现，NO是必不可少的细胞内生长控制MAB在巨噬细胞中的抑制剂测定使用iNOS缺陷型细胞。此外，在MAB感染小鼠之前预处理rIFN-β增加了感染后第1天肺中NO的产生，并促进了第5天的细菌清除。但当氯膦酸盐脂质体作用于肺泡巨噬细胞时，rIFN-β对肺内细菌清除无促进作用。此外，我们发现胞质受体核苷酸结合寡聚化结构域2（NOD 2）是MAB诱导的TANK结合激酶1（TBK 1）磷酸化和IFN-β基因在巨噬细胞中表达所必需的。最后，在NOD 2缺陷小鼠的肺中，由NO水平降低引起的细菌负荷的增加被rIFN-β治疗逆转。总的来说，我们的研究结果表明，I型干扰素作为NOD 2诱导的NO产生的巨噬细胞的中介，从而有助于宿主防御单克隆抗体感染。
Mycobacterium abscessus (MAB) is one of the rapidly growing, multidrug-resistant non-tuberculous mycobacteria (NTM) causing various diseases including pulmonary disorder. Although it has been known that type I interferons (IFNs) contribute to host defense against bacterial infections, the role of type I IFNs against MAB infection is still unclear. In the present study, we show that rIFN-β treatment reduced the intracellular growth of MAB in macrophages. Deficiency of IFN-α/β receptor (IFNAR) led to the reduction of nitric oxide (NO) production in MAB-infected macrophages. Consistently, rIFN-β treatment enhanced the expression of iNOS gene and protein, and NO production in response to MAB. We also found that NO is essential for the intracellular growth control of MAB within macrophages in an inhibitor assay using iNOS-deficient cells. In addition, pretreatment of rIFN-β before MAB infection in mice increased production of NO in the lungs at day 1 after infection and promoted the bacterial clearance at day 5. However, when alveolar macrophages were depleted by treatment of clodronate liposome, rIFN-β did not promote the bacterial clearance in the lungs. Moreover, we found that a cytosolic receptor nucleotide-binding oligomerization domain 2 (NOD2) is required for MAB-induced TANK binding kinase 1 (TBK1) phosphorylation and IFN-β gene expression in macrophages. Finally, increase in the bacterial loads caused by reduction of NO levels was reversed by rIFN-β treatment in the lungs of NOD2-deficient mice. Collectively, our findings suggest that type I IFNs act as an intermediator of NOD2-induced NO production in macrophages and thus contribute to host defense against MAB infection.
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