Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
EMBO Rep. 2017 Dec;18(12):2144-2159. doi: 10.15252/embr.201744121. Epub 2017 Nov 2.
Immunity to mycobacteria involves the formation of granulomas, characterized by a unique macrophage (MΦ) species, so-called multinucleated giant cells (MGC). It remains unresolved whether MGC are beneficial to the host, that is, by prevention of bacterial spread, or whether they promote mycobacterial persistence. Here, we show that the prototypical antimycobacterial molecule nitric oxide (NO), which is produced by MGC in excessive amounts, is a double-edged sword. Next to its antibacterial capacity, NO propagates the transformation of MΦ into MGC, which are relatively permissive for mycobacterial persistence. The mechanism underlying MGC formation involves NO-induced DNA damage and impairment of p53 function. Moreover, MGC have an unsurpassed potential to engulf mycobacteria-infected apoptotic cells, which adds a further burden to their antimycobacterial capacity. Accordingly, mycobacteria take paradoxical advantage of antimicrobial cellular efforts by driving effector MΦ into a permissive MGC state.
针对分枝杆菌的免疫反应涉及到肉芽肿的形成，其特征是存在一种独特的巨噬细胞（MΦ），即所谓的多核巨细胞（MGC）。目前仍不清楚 MGC 是否对宿主有益，也就是说，它们是通过防止细菌扩散，还是促进分枝杆菌的持续存在。在这里，我们表明，由 MGC 过量产生的典型抗分枝杆菌分子一氧化氮（NO）是一把双刃剑。除了其抗菌能力外，NO 还会促使 MΦ 转化为 MGC，MGC 对分枝杆菌的持续存在相对宽容。MGC 形成的机制涉及到 NO 诱导的 DNA 损伤和 p53 功能的损害。此外，MGC 吞噬感染分枝杆菌的凋亡细胞的潜力无与伦比，这给它们的抗分枝杆菌能力增加了额外的负担。因此，分枝杆菌通过将效应 MΦ 驱动到允许的 MGC 状态，从而利用了抗菌细胞的努力，这是一种矛盾的优势。
