Olguín Jonadab E, Corano-Arredondo Edmundo, Hernández-Gómez Victoria, Rivera-Montoya Irma, Rodríguez Mario A, Medina-Andrade Itzel, Arendse Berenice, Brombacher Frank, Terrazas Luis I
Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Estado de México, Mexico.
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Estado de México, Mexico.
Pathogens. 2024 Feb 13;13(2):169. doi: 10.3390/pathogens13020169.
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 , 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 or cre/LoxP). While 100% of -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 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 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 -infected LysMcreIL-4Rα 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 infection. Thus, the absence of these suppressor cells is one of the leading mechanisms to control experimental cysticercosis successfully.
为了确定白细胞介素-4/白细胞介素13受体在替代性活化巨噬细胞（AAM或M2）发育中的作用及其在调节对蠕虫寄生虫肠外阶段免疫中的作用，我们在缺乏白细胞介素-4受体α基因（IL-4Rα）的小鼠品系以及巨噬细胞/中性粒细胞特异性IL-4Rα缺陷小鼠品系（LysMcreIL-4Rα或cre/LoxP）中追踪感染情况。虽然100%感染的IL-4Rα（野生型）小鼠体内寄生虫负荷量大，但超过50%的IL-4Rα小鼠清除了感染。约88%的LysMcreIL-4Rα小鼠对感染表现出无菌免疫。其余少数感染的cre/LoxP小鼠腹腔内幼虫数量最少。野生型小鼠无法控制感染与抗原特异性Th2型反应有关，其IgG1、IL-4、IL-13和总IgE水平较高，一氧化氮产生减少，精氨酸酶活性增加。相比之下，IL-4Rα半抗性小鼠表现出Th1/Th2联合反应。此外，野生型小鼠的巨噬细胞中精氨酸酶-1和RELM-α的转录本更高，并且PD-L2表达增加，对抗CD3/CD28刺激的T细胞具有强大的抑制活性；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小鼠均未完全发育出AAM，也未对CD3/CD28刺激的T细胞表现出抑制活性，PDL2表达降低。此外，T-CD8而非T-CD4细胞在野生型和IL-4Rα小鼠中表现出抑制表型，Tim-3和PD1表达增加，而在感染的LysMcreIL-4Rα小鼠中不存在这种情况。这些发现证明了白细胞介素-4信号通路在囊尾蚴病期间维持AAM及其抑制活性方面的关键作用，表明AAM在促进感染易感性方面起关键作用。因此，这些抑制细胞的缺失是成功控制实验性囊尾蚴病的主要机制之一。
