ISP, Infectiologie et Santé Publique, INRA, Université de Tours, Nouzilly, France.
Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, BP 64182, Toulouse, France.
Front Immunol. 2019 Dec 17;10:2913. doi: 10.3389/fimmu.2019.02913. eCollection 2019.
, the causative agent of leprosy, is unique amongst human pathogens in its capacity to produce the virulence factor phenolic glycolipid (PGL)-I. In addition to mediating bacterial tropism for neurons, PGL-I interacts with Complement Receptor (CR)3 on macrophages (MPs) to promote infection. We demonstrate here that PGL-I binding to CR3 also enhances bacterial invasion of both polymorphonuclear neutrophils (PMNs) and dendritic cells (DCs). Moreover, in all cell types CR3 engagement by PGL-I activates the Syk tyrosine kinase, inducing calcineurin-dependent nuclear translocation of the transcription factor NFATc. This selectively augments the production of IL-2 by DCs, IL-10 by PMNs and IL-1β by MPs. In intranasally-infected mice PGL-I binding to CR3 heightens mycobacterial phagocytosis by lung PMNs and MPs, and stimulates NFATc-controlled production of Syk-dependent cytokines. Our study thus identifies the CR3-Syk-NFATc axis as a novel signaling pathway activated by PGL-I in innate immune cells, rewiring host cytokine responses to .
麻风分枝杆菌是麻风病的病原体，它具有产生酚甘油酯-I（PGL-I）这种毒力因子的能力，在人类病原体中是独一无二的。除了介导细菌对神经元的趋向性外，PGL-I 还与巨噬细胞（MPs）上的补体受体（CR）3 相互作用，促进感染。我们在这里证明，PGL-I 与 CR3 的结合也增强了多形核粒细胞（PMN）和树突状细胞（DC）的细菌入侵。此外，在所有细胞类型中，PGL-I 与 CR3 的结合激活了 Syk 酪氨酸激酶，诱导转录因子 NFATc 的钙调神经磷酸酶依赖性核易位。这选择性地增加了 DC 产生 IL-2、PMN 产生 IL-10 和 MPs 产生 IL-1β。在鼻内感染的小鼠中，PGL-I 与 CR3 的结合增强了肺 PMN 和 MPs 对分枝杆菌的吞噬作用，并刺激了 NFATc 控制的 Syk 依赖性细胞因子的产生。因此，我们的研究确定了 CR3-Syk-NFATc 轴作为 PGL-I 在先天免疫细胞中激活的新信号通路，重新布线宿主细胞因子反应以应对 。
