Exosomal microRNA let-7-5p from Taenia pisiformis Cysticercus Prompted Macrophage to M2 Polarization through Inhibiting the Expression of C/EBP δ

Abstract

Cysticercus pisiformis, the larval stage of Taenia pisiformis, causes serious illness in rabbits that severely impacts the rabbit breeding industry. An inhibitive Th2 immune response can be induced by let-7-enriched exosomes derived from T. pisiformis cysticercus. However, the underlying molecular mechanisms are not completely understood. Here, we report that exosomal miR-let-7-5p released by T. pisiformis cysticercus played a critical role in the activation of M2 macrophages. We found that overexpression of let-7-5p in M1 macrophages decreased M1 phenotype expression while promoting polarization to the M2 phenotype, which is consistent with experimental data in exosome-treated macrophages alone. In contrast, knockdown of let-7-5p in exosome-like vesicles promoted M1 polarization and decreased M2 phenotype expression. Furthermore, down-regulation of transcription factor CCAAT/enhancer-binding protein (C/EBP)-δ resulted in the decrease of M1 phenotype markers and increase of M2 phenotype markers. These results suggested that let-7 enriched in exosome-like vesicles from T. pisiformis metacestodes can induce M2 macrophage polarization via targeting C/EBP δ, which may be involved in macrophage polarization induced by T. pisiformis metacestodes. The finding helps to expand our knowledge of the molecular mechanism of immunosuppression and Th2 immune response induced by metacestodes.

Macrophage regulation & function in helminth infection

“…by modulating the early proinflammatory response of macrophages towards the parasite. Macrophage classical activation is also suppressed by Taenia pisiformis exosomes, which deliver miRNA let7-5p to inhibit macrophage Cebpd mRNA and thus reduce Il12 and Nos2 gene expression [145]. Interestingly, exosomes containing M1-suppressive miRNA were derived from cysticerci of T. pisiformis, suggesting that it is indeed advantageous for early parasite stages to target classical activation of macrophages.…”

Identification and Expression Profiling of Circulating MicroRNAs in Serum of Cysticercus pisiformis-Infected Rabbits

“…miRNA let-7-5p from C. pisiformis exosomes has been reported to decrease M1 phenotype expression while promoting polarization to the M2 phenotype through inhibition of the expression of transcription factor CCAAT/enhancer-binding protein (C/EBP)-δ. However, let-7-5p was also detected in rabbit serum at 2 months post infection, and may be released into rabbit serum through C. pisiformis exosomes [38].…”

Role of Fasciola hepatica Small RNAs in the Interaction With the Mammalian Host

“…Additionally, sjabantam and sja-miR-125b were found to induce Th2 key mediator, TNF-a in macrophages in vitro and in vivo, facilitating parasite development and egg deposition (Liu et al, 2019). Furthermore, parasite-derived let-7 has been predicted to regulate the Wnt signaling pathway and T/B cell activation in mouse genes, and to induce a Th2 immune response in macrophages treated with miRNA mimics in cestodes (Ancarola et al, 2017;Wang et al, 2021). Th2 modulation is a common theme in parasite immune-evasion (Coakley et al, 2016).…”