Extracellular Vesicles Released from Mycobacterium tuberculosis-Infected Neutrophils Promote Macrophage Autophagy and Decrease Intracellular Mycobacterial Survival.
Extracellular Vesicles Released from Mycobacterium tuberculosis-Infected Neutrophils Promote Macrophage Autophagy and Decrease Intracellular Mycobacterial Survival.
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DOI：
10.3389/fimmu.2018.00272
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发表时间：
2018
影响因子：
7.3
通讯作者：
Estrada-García I
中科院分区：
文献类型：
--
作者：
Alvarez-Jiménez VD;Leyva-Paredes K;García-Martínez M;Vázquez-Flores L;García-Paredes VG;Campillo-Navarro M;Romo-Cruz I;Rosales-García VH;Castañeda-Casimiro J;González-Pozos S;Hernández JM;Wong-Baeza C;García-Pérez BE;Ortiz-Navarrete V;Estrada-Parra S;Serafín-López J;Wong-Baeza I;Chacón-Salinas R;Estrada-García I
结核病是由结核分枝杆菌(Mtb)引起的传染病。在肺部，巨噬细胞和中性粒细胞是第一批与感染分枝杆菌接触的免疫细胞。中性粒细胞是一种吞噬细胞，通过几种机制杀死微生物，包括溶酶体中发现的裂解酶和抗菌肽，以及产生活性氧物种。中性粒细胞还向细胞外环境释放细胞外小泡(EV)(直径100-1,000 nm)；这些EV由包裹着亲水核心的脂双层组成，参与细胞间的通讯。我们先前证明了体外感染Mtb H37Rv的人中性粒细胞释放EV-TB，但这些EV对其他与控制Mtb感染相关的细胞，如巨噬细胞的影响尚未完全分析。在这项研究中，我们研究了由非刺激的人中性粒细胞(EV-NS)产生的EV，以及由活化剂(PMA)刺激的中性粒细胞产生的EV，PMA是一种来自细菌蛋白的多肽(FMLF)或Mtb，并观察到这四种EV的大小不同。在EV-TB中检测到Toll样受体2/6的配体，与其他EV相比，EV-TB中共刺激分子CD80的表达略有增加，CD86的表达更高，人巨噬细胞产生更多的肿瘤坏死因子-α和IL-6，以及更低的转化生长因子-β。EV-TB可降低巨噬细胞内Mtb的含量，增加巨噬细胞内超氧阴离子的产生。TLR2/6的连接和超氧阴离子的产生是已知的自噬的诱导者；因此，我们发现EV-TB诱导巨噬细胞中自噬相关标记物LC3-II的表达增加，并在感染的巨噬细胞内与Mtb共存。当Wortmannin抑制细胞自噬时，细胞内分枝杆菌载量增加。综上所述，我们的结果表明，中性粒细胞在不同的激活剂作用下产生不同的EV，EV-TB通过早期产生超氧阴离子和自噬诱导激活巨噬细胞，促进细胞内Mtb的清除，这是中性粒细胞来源的EV在Mtb免疫应答中的新作用。
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb). In the lungs, macrophages and neutrophils are the first immune cells that have contact with the infecting mycobacteria. Neutrophils are phagocytic cells that kill microorganisms through several mechanisms, which include the lytic enzymes and antimicrobial peptides that are found in their lysosomes, and the production of reactive oxygen species. Neutrophils also release extracellular vesicles (EVs) (100–1,000 nm in diameter) to the extracellular milieu; these EVs consist of a lipid bilayer surrounding a hydrophilic core and participate in intercellular communication. We previously demonstrated that human neutrophils infected in vitro with Mtb H37Rv release EVs (EV-TB), but the effect of these EVs on other cells relevant for the control of Mtb infection, such as macrophages, has not been completely analyzed. In this study, we characterized the EVs produced by non-stimulated human neutrophils (EV-NS), and the EVs produced by neutrophils stimulated with an activator (PMA), a peptide derived from bacterial proteins (fMLF) or Mtb, and observed that the four EVs differed in their size. Ligands for toll-like receptor (TLR) 2/6 were detected in EV-TB, and these EVs favored a modest increase in the expression of the co-stimulatory molecules CD80, a higher expression of CD86, and the production of higher amounts of TNF-α and IL-6, and of lower amounts of TGF-β, in autologous human macrophages, compared with the other EVs. EV-TB reduced the amount of intracellular Mtb in macrophages, and increased superoxide anion production in these cells. TLR2/6 ligation and superoxide anion production are known inducers of autophagy; accordingly, we found that EV-TB induced higher expression of the autophagy-related marker LC3-II in macrophages, and the co-localization of LC3-II with Mtb inside infected macrophages. The intracellular mycobacterial load increased when autophagy was inhibited with wortmannin in these cells. In conclusion, our results demonstrate that neutrophils produce different EVs in response to diverse activators, and that EV-TB activate macrophages and promote the clearance of intracellular Mtb through early superoxide anion production and autophagy induction, which is a novel role for neutrophil-derived EVs in the immune response to Mtb.
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影响因子：
3.2
作者：
Gonzalez-Cano, Patricia;Mondragon-Flores, Ricardo;Estrada-Garcia, Iris
通讯作者：
Estrada-Garcia, Iris
影响因子：
5.3
作者：
Nomura, S;Tandon, NN;Kambayashi, J
通讯作者：
Kambayashi, J
影响因子：
3.3
作者：
Jung, Chang Hwa;Jun, Chang Bong;Kim, Do-Hyung
通讯作者：
Kim, Do-Hyung
影响因子：
3.6
作者：
Lee, Pamela P. W.;Chan, Koon-Wing;Lau, Yu-Lung
通讯作者：
Lau, Yu-Lung
影响因子：
6.4
作者：
JONES, GS;AMIRAULT, HJ;ANDERSEN, BR
通讯作者：
ANDERSEN, BR