PDF(Pubmed)
Abstract：
To determine the role that the IL-4/IL13 receptor plays in the development of alternatively activated macrophages (AAM or M2) and their role in the regulation of immunity to the extraintestinal phase of the helminth parasite Taenia crassiceps, we followed the infection in a mouse strain lacking the IL-4Rα gene (IL-4Rα-/-) and in the macrophage/neutrophil-specific IL-4Rα-deficient mouse strain (LysMcreIL-4Rα-/lox or cre/LoxP). While 100% of T. crassiceps-infected IL-4Rα+/+ (WT) mice harbored large parasite loads, more than 50% of th eIL-4Rα-/- mice resolved the infection. Approximately 88% of the LysMcreIL-4Rα-/lox mice displayed a sterilizing immunity to the infection. The remaining few infected cre/LoxP mice displayed the lowest number of larvae in their peritoneal cavity. The inability of the WT mice to control the infection was associated with antigen-specific Th2-type responses with higher levels of IgG1, IL-4, IL-13, and total IgE, reduced NO production, and increased arginase activity. In contrast, IL-4Rα-/- semi-resistant mice showed a Th1/Th2 combined response. Furthermore, macrophages from the WT mice displayed higher transcripts for Arginase-1 and RELM-α, as well as increased expression of PD-L2 with robust suppressive activity over anti-CD3/CD28 stimulated T cells; all of these features are associated with the AAM or M2 macrophage phenotype. In contrast, both the IL-4Rα-/- and LysMcreIL-4Rα-/lox mice did not fully develop AAM or display suppressive activity over CD3/CD28 stimulated T cells, reducing PDL2 expression. Additionally, T-CD8+ but no T-CD4+ cells showed a suppressive phenotype with increased Tim-3 and PD1 expression in WT and IL-4Rα-/-, which were absent in T. crassiceps-infected LysMcreIL-4Rα-/lox mice. These findings demonstrate a critical role for the IL-4 signaling pathway in sustaining AAM and its suppressive activity during cysticercosis, suggesting a pivotal role for AAM in favoring susceptibility to T. crassiceps infection. Thus, the absence of these suppressor cells is one of the leading mechanisms to control experimental cysticercosis successfully.
摘要：
为了确定IL-4/IL13受体在交替激活的巨噬细胞（AAM或M2）的发育中的作用，以及它们在调节对蠕虫寄生虫的肠外阶段的免疫力中的作用，我们追踪了缺乏IL-4Rα基因的小鼠品系(IL-4Rα-/-)和巨噬细胞/中性粒细胞特异性IL-4Rα缺陷型小鼠品系(LysMcreIL-4Rα-/lox或cre/LoxP)的感染.而100％的T.crassiceps感染的IL-4Rα/（WT）小鼠携带大量寄生虫，超过50%的eIL-4Rα-/-小鼠解决了感染。大约88%的LysMcreIL-4Rα-/lox小鼠表现出对感染的灭菌免疫。其余几只受感染的cre/LoxP小鼠在其腹膜腔中显示出最低数量的幼虫。WT小鼠无法控制感染与抗原特异性Th2型反应相关，具有较高水平的IgG1，IL-4，IL-13和总IgE，减少NO产生，和增加的精氨酸酶活性。相比之下,IL-4Rα-/-半抗性小鼠显示Th1/Th2组合应答。此外，来自WT小鼠的巨噬细胞显示出更高的精氨酸酶-1和RELM-α转录本，以及与抗CD3/CD28刺激的T细胞相比具有强大抑制活性的PD-L2的表达增加;所有这些特征都与AAM或M2巨噬细胞表型相关。相比之下,IL-4Rα-/-和LysMcreIL-4Rα-/lox小鼠均未完全发展AAM或显示对CD3/CD28刺激的T细胞的抑制活性，减少PDL2表达。此外,T-CD8+但无T-CD4+细胞显示抑制表型，在WT和IL-4Rα-/-中Tim-3和PD1表达增加，在T.crassiceps感染的LysMcreIL-4Rα-/lox小鼠中不存在。这些发现证明了IL-4信号通路在囊虫病期间维持AAM及其抑制活性中的关键作用。提示AAM在有利于T.crusiceps感染的易感性中的关键作用。因此，这些抑制细胞的缺失是成功控制实验性囊虫病的主要机制之一。
