Division of Parasitology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow 226031, India.
Academy of Scientific and Innovative Research, Anusandhan Bhawan, New Delhi 110001, India; and.
J Immunol. 2018 Aug 1;201(3):957-970. doi: 10.4049/jimmunol.1800062. Epub 2018 Jun 15.
IL-1R/TLR signaling plays a significant role in sensing harmful foreign pathogens and mounting effective innate and adaptive immune responses. However, the precise mechanism by which an obligate intramacrophagic pathogen, breaches IL-1R/TLR signaling and host-protective immunity remains obscure. In this study, we report the novel biphasic role of Toll-interacting protein (Tollip), a negative regulator of the IL-1R/TLR pathway, in the disease progression of experimental visceral leishmaniasis. We observed that during early hours of infection, induced phosphorylation of IRAK-1, resulting in the release of Tollip from the IL-1R-associated kinase (IRAK)-1 complex in J774 macrophages, which then acted as an endocytic adaptor on cell surface IL-1R1 and promoted its lysosomal degradation. In the later stage, Tollip shuttled back to IRAK-1, thereby inhibiting IRAK-1 phosphorylation in association with IRAK-M to neutralize downstream TLR signaling in infected macrophages. Moreover, during late infection, enhanced nuclear translocation and recruitment of transcription factors early growth response protein 2, NF erythroid 2-related factor 2, and Ahr on Tollip promoter for its induction. Small interfering RNA-mediated silencing of Tollip in infected macrophages significantly enhanced NF-κB activation and induced host-defensive IL-12 and TNF-α synthesis, thereby reducing amastigote multiplication. Likewise, abrogation of Tollip in infected BALB/c mice resulted in STAT-1-, IRF-1-, and NF-κB-mediated upregulation of host-protective cytokines and reduced organ parasite burden, thereby implicating its role in disease aggravation. Taken together, we conclude that exploited the multitasking function of Tollip for its own establishment through downregulating IL-1R1/TLR signaling in macrophages.
IL-1R/TLR 信号在感知有害的外来病原体并引发有效的先天和适应性免疫反应方面发挥着重要作用。然而，对于一种必需的巨噬细胞内病原体来说，其破坏 IL-1R/TLR 信号和宿主保护性免疫的确切机制仍不清楚。在这项研究中，我们报告了 Toll 相互作用蛋白（Tollip）的新的双相作用，Tollip 是 IL-1R/TLR 途径的负调节剂，在实验性内脏利什曼病的疾病进展中发挥作用。我们观察到，在感染的早期， 诱导 IRAK-1 的磷酸化，导致 Tollip 从 J774 巨噬细胞中的 IL-1R 相关激酶（IRAK）-1 复合物中释放出来，然后作为细胞表面 IL-1R1 的内吞衔接子，并促进其溶酶体降解。在后期，Tollip 重新转移到 IRAK-1 上，从而抑制 IRAK-1 与 IRAK-M 的磷酸化，以中和感染巨噬细胞中的下游 TLR 信号。此外，在晚期感染中， 增强了转录因子早期生长反应蛋白 2、NF 红细胞 2 相关因子 2 和 Ahr 在 Tollip 启动子上的核易位和募集，以诱导其表达。用 Tollip 的小干扰 RNA 对感染的巨噬细胞进行沉默，显著增强了 NF-κB 的激活，并诱导了宿主防御性的 IL-12 和 TNF-α 的合成，从而减少了无鞭毛体的增殖。同样，在感染的 BALB/c 小鼠中敲除 Tollip 导致 STAT-1、IRF-1 和 NF-κB 介导的宿主保护性细胞因子的上调，并减少了器官寄生虫负担，从而表明其在疾病恶化中的作用。综上所述，我们得出结论， 通过下调巨噬细胞中的 IL-1R1/TLR 信号， 利用了 Tollip 的多任务功能来实现自身的建立。
