Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection.
Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection.
复制标题
DOI：
10.1038/ncomms14642
复制
发表时间：
2017-03-06
影响因子：
16.6
通讯作者：
Dionne MS
中科院分区：
文献类型：
--
作者：
Péan CB;Schiebler M;Tan SW;Sharrock JA;Kierdorf K;Brown KP;Maserumule MC;Menezes S;Pilátová M;Bronda K;Guermonprez P;Stramer BM;Andres Floto R;Dionne MS
结核分枝杆菌仍然是对人类健康的全球性威胁，但调节免疫的分子机制仍然知之甚少。细胞因子可以促进或抑制巨噬细胞内分枝杆菌的存活，其潜在机制是宿主定向治疗的潜在靶点。在这里，我们发现细胞因子stat信号通过ATG2抑制来解除脂滴的调节，从而促进巨噬细胞内分枝杆菌的存活。在海洋分枝杆菌感染的果蝇中，分枝杆菌诱导的由未配对家族细胞因子引发的STAT活性降低了Atg2的表达，从而允许脂滴的解除。Atg2表达增加或巨噬细胞甘油三酯生物合成减少，使感染吞噬细胞中的脂质沉积正常化，并减少细胞内活分枝杆菌的数量。在人巨噬细胞中，添加IL-6促进分枝杆菌存活和bcg诱导的脂质积累的机制类似，但可能不完全相同。我们的研究结果揭示了Atg2调控是细胞因子控制果蝇脂滴稳态和抵抗分枝杆菌感染的机制。细胞因子及其相关途径可以影响巨噬细胞中结核分枝杆菌的存活，代表了宿主定向治疗的潜在靶点。在这里，p<s:1>等人表明细胞因子stat信号通过解除脂滴稳态调节促进巨噬细胞内分枝杆菌的存活。
Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survival inside macrophages and the underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplets via ATG2 repression. In Drosophila infected with Mycobacterium marinum, mycobacterium-induced STAT activity triggered by unpaired-family cytokines reduces Atg2 expression, permitting deregulation of lipid droplets. Increased Atg2 expression or reduced macrophage triglyceride biosynthesis, normalizes lipid deposition in infected phagocytes and reduces numbers of viable intracellular mycobacteria. In human macrophages, addition of IL-6 promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2 regulation as a mechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infection in Drosophila. Cytokines and their associated pathways can affect survival of Mycobacterium tuberculosis in macrophages, representing potential targets for host-directed therapies. Here, Péan et al. show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplet homeostasis.