Glamočlija Sofija, Sabljić Ljiljana, Tomić Sergej, Đokić Jelena, Radulović Nataša, Gruden-Movsesijan Alisa, Kosanović Maja
Institute for the Application of Nuclear Energy INEP University of Belgrade Republic of Serbia.
Institute of Molecular Genetics and Genetic Engineering IMGGE University of Belgrade Republic of Serbia.
Int J Parasitol. 2025 May;55(6):299-315. doi: 10.1016/j.ijpara.2025.01.008. Epub 2025 Jan 20.
The helminth Trichinella spiralis, through its excretory-secretory (ES L1) products, induces immune regulatory mechanisms that modulate the host's immune response not only to itself, but also to bystander antigens, foreign or self in origin, which can result in the alleviation of inflammatory diseases. Under the influence of ES L1, dendritic cells (DCs) acquire a tolerogenic phenotype and the capacity to induce Th2 and regulatory responses. Since ES L1 products represent a complex mixture of proteins and extracellular vesicles (TsEVs) the aim of this study was to investigate the impact of TsEVs, isolated from ES L1 products, on phenotypic and functional characteristics of DCs and to elucidate whether TsEVs could reproduce the immunomodulatory effects of the complete ES L1 product. Monocyte-derived DCs treated with TsEVs acquired semi-matured phenotypes, characterized by low expression of human leukocyte antigen - DR isotype (HLA-DR), cluster of differentiation (CD) 86 (CD86), and CD40, moderate expression of CD83 and C-C chemokine receptor type 7 (CCR7), and increased expression of tolerogenic markers indoleamine 2,3-dioxygenase 1 (IDO-1) and immunoglobulin-like transcript 3 (ILT3), together with the unchanged production of IL-12 and IL-23, and elevated production of IL-10 and transforming growth factor (TGF)-β, compared with controls. Gene expression analysis of TsEV-treated DCs revealed elevated levels of mTOR, Ahr, NF-κB2, RelB, SOCS1 and SOCS3, which participate in signaling pathways involved in DC maturation and the subsequent regulation of release of both anti-inflammatory and pro-inflammatory cytokines. TsEVs promoted the capacity of DCs to drive polarization of Th2 and anti-inflammatory responses, and impaired their capacity to induce Th1/Th17 polarization. Moreover, TsEV-treated DCs possessed a high capacity to induce conventional FoxP3 + regulatory T cells, as well as unconventional T regulatory (Tr1) cells. Tolerogenic properties of TsEV-treated DCs were retained even after challenge with a pro-inflammatory stimulus. These findings highlight the potential of TsEVs to induce immune tolerance, suggesting their potential use as therapeutics for the treatment of inflammatory disorders.
旋毛虫通过其排泄分泌（ES L1）产物诱导免疫调节机制，该机制不仅可调节宿主对其自身的免疫反应，还可调节对旁观者抗原（来源于外源或自身）的免疫反应，这可能导致炎症性疾病的减轻。在ES L1的影响下，树突状细胞（DC）获得致耐受性表型以及诱导Th2和调节性反应的能力。由于ES L1产物是蛋白质和细胞外囊泡（TsEV）的复杂混合物，本研究的目的是研究从ES L1产物中分离出的TsEV对DC表型和功能特征的影响，并阐明TsEV是否能够重现完整ES L1产物的免疫调节作用。用TsEV处理的单核细胞来源的DC获得了半成熟表型，其特征为人白细胞抗原-DR同种型（HLA-DR）、分化簇（CD）86（CD86）和CD40的低表达，CD83和C-C趋化因子受体7型（CCR7）的中度表达，以及致耐受性标志物吲哚胺2,3-双加氧酶1（IDO-1）和免疫球蛋白样转录物3（ILT3）的表达增加，与对照组相比，IL-12和IL-23的产生未改变，而IL-10和转化生长因子（TGF）-β的产生增加。对用TsEV处理的DC进行基因表达分析发现，mTOR、芳香烃受体（Ahr）、NF-κB2、RelB、细胞因子信号转导抑制因子1（SOCS1）和细胞因子信号转导抑制因子3（SOCS3）的水平升高，它们参与DC成熟以及随后抗炎和促炎细胞因子释放调节的信号通路。TsEV促进了DC驱动Th2和抗炎反应极化的能力，并损害了它们诱导Th1/Th17极化的能力。此外，用TsEV处理的DC具有诱导常规FoxP3 +调节性T细胞以及非常规T调节（Tr1）细胞的高能力。即使在用促炎刺激物攻击后，用TsEV处理的DC的致耐受性特性仍得以保留。这些发现突出了TsEV诱导免疫耐受的潜力，表明它们在治疗炎症性疾病方面的潜在用途。
