Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina.
Front Immunol. 2018 Apr 23;9:859. doi: 10.3389/fimmu.2018.00859. eCollection 2018.
During the acute phase of infection, macrophages can act as host cells for the parasites as well as effector cells in the early anti-parasitic immune response. Thus, the targeting of specific signaling pathways could modulate macrophages response to restrict parasite replication and instruct an appropriate adaptive response. Recently, it has become evident that Wnt signaling has immunomodulatory functions during inflammation and infection. Here, we tested the hypothesis that during infection, the activation of Wnt signaling pathway in macrophages plays a role in modulating the inflammatory/tolerogenic response and therefore regulating the control of parasite replication. In this report, we show that early after infection of bone marrow-derived macrophages (BMM), β-catenin was activated and Wnt3a, Wnt5a, and some Frizzled receptors as well as Wnt/β-catenin pathway's target genes were upregulated, with Wnt proteins signaling sustaining the activation of Wnt/β-catenin pathway and then activating the Wnt/Ca pathway. Wnt signaling pathway activation was critical to sustain the parasite's replication in BMM; since the treatments with specific inhibitors of β-catenin transcriptional activation or Wnt proteins secretion limited the parasite replication. Mechanistically, inhibition of Wnt signaling pathway armed BMM to fight against by inducing the production of pro-inflammatory cytokines and indoleamine 2,3-dioxygenase activity and by downregulating arginase activity. Likewise, pharmacological inhibition of the Wnts' interaction with its receptors controlled the parasite replication and improved the survival of lethally infected mice. It is well established that infection activates a plethora of signaling pathways that ultimately regulate immune mediators to determine the modulation of a defined set of effector functions in macrophages. In this study, we have revealed a new signaling pathway that is activated by the interaction between protozoan parasites and host innate immunity, establishing a new conceptual framework for the development of new therapies.
在感染的急性期，巨噬细胞可以作为寄生虫的宿主细胞，也是早期抗寄生虫免疫反应中的效应细胞。因此，靶向特定的信号通路可以调节巨噬细胞的反应，限制寄生虫的复制，并指导适当的适应性反应。最近，Wnt 信号在炎症和感染过程中具有免疫调节功能已变得明显。在这里，我们检验了这样一个假设，即在感染过程中，巨噬细胞中 Wnt 信号通路的激活在调节炎症/耐受反应中发挥作用，从而调节寄生虫复制的控制。在本报告中，我们显示在骨髓来源的巨噬细胞（BMM）感染后早期，β-连环蛋白被激活，Wnt3a、Wnt5a 和一些卷曲受体以及 Wnt/β-连环蛋白途径的靶基因上调，Wnt 蛋白信号维持 Wnt/β-连环蛋白途径的激活，然后激活 Wnt/Ca 途径。Wnt 信号通路的激活对于维持 BMM 中的寄生虫复制至关重要；因为特异性β-连环蛋白转录激活或 Wnt 蛋白分泌抑制剂的处理限制了寄生虫的复制。从机制上讲，抑制 Wnt 信号通路武装 BMM 对抗寄生虫，通过诱导产生促炎细胞因子和吲哚胺 2,3-双加氧酶活性，并下调精氨酸酶活性。同样，Wnts 与其受体相互作用的药理学抑制控制寄生虫复制并提高致死性感染小鼠的存活率。众所周知，寄生虫感染激活了大量的信号通路，最终调节免疫介质，以确定巨噬细胞中一组特定效应功能的调节。在这项研究中，我们揭示了一条新的信号通路，该通路被原生动物寄生虫与宿主先天免疫之间的相互作用激活，为开发新疗法建立了一个新的概念框架。
