New insights into the immunomodulatory potential of sialic acid on monocyte-derived dendritic cells.

IF 4.6 2区 医学 Q2 IMMUNOLOGY Cancer Immunology, Immunotherapy Pub Date : 2024-11-02 DOI:10.1007/s00262-024-03863-7
Zélia Silva, João Amorim Rabaça, Vanessa Luz, Rita Adubeiro Lourenço, Mariolina Salio, Alexandra Couto Oliveira, Pedro Bule, Sebastian Springer, Paula Alexandra Videira
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Abstract

Sialic acids at the cell surface of dendritic cells (DCs) play an important immunomodulatory role, and their manipulation enhances DC maturation, leading to heightened T cell activation. Particularly, at the molecular level, the increased stability of surface MHC-I molecules in monocyte-derived DCs (MoDCs) underpins an improved DC: T cell interaction. In this study, we focused on the impact of sialic acid remodelling by treatment with Clostridium perfringens sialidase on MoDCs' phenotypic and functional characteristics. Our investigation juxtaposes this novel approach with the conventional cytokine-based maturation regimen commonly employed in clinical settings.Notably, C. perfringens sialidase remarkably increased MHC-I levels compared to other sialidases having different specificities, supporting the idea that higher MHC-I is due to the cleavage of specific sialoglycans on cell surface proteins. Sialidase treatment induced rapid elevated surface expression of MHC-I, MHC-II and CD40 within an hour, a response not fully replicated by 48 h cytokine cocktail treatment. These increases were also observable 48 h post sialidase treatment. While CD86 and PD-L1 showed significant increases after 48 h of cytokine maturation, 48 h post sialidase treatment showed a higher increase in CD86 and shorter increase in PD-L1. CCR-7 expression was significantly increased 48 h after sialidase treatment but not significantly affected by cytokine maturation. Both treatments promoted higher secretion of the IL-12 cytokine. However, the cytokine cocktail induced a more pronounced IL-12 production. SNA lectin staining analysis demonstrated that the sialic acid profile is significantly altered by sialidase treatment, but not by the cytokine cocktail, which causes only slight sialic acid upregulation. Notably, the lipid-presenting molecules CD1a, CD1b and CD1c remained unaffected by sialidase treatment in MoDCs, a finding also further supported by experiments performed on C1R cells. Inhibition of endogenous sialidases Neu1 and Neu3 during MoDC differentiation did not affect surface MHC-I expression and cytokine secretion. Yet, sialidase activity in MoDCs was minimal, suggesting that sialidase inhibition does not significantly alter MHC-I-related functions. Our study highlights the unique maturation profile induced by sialic acid manipulation in MoDCs. These findings provide insights into the potential of sialic acid manipulation as a rapid immunomodulatory strategy, offering promising avenues for targeted interventions in inflammatory contexts.

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关于单核细胞衍生树突状细胞上的唾液酸免疫调节潜力的新见解。
树突状细胞(DC)细胞表面的唾液酸起着重要的免疫调节作用,操纵唾液酸可提高 DC 的成熟度,从而增强 T 细胞的活化。特别是在分子水平上,单核细胞衍生 DC(MoDCs)表面 MHC-I 分子稳定性的增加是改善 DC 与 T 细胞相互作用的基础。在本研究中,我们重点研究了用产气荚膜梭状芽孢杆菌硅糖苷酶处理硅酸重塑对 MoDCs 表型和功能特征的影响。值得注意的是,与其他具有不同特异性的硅糖苷酶相比,产气荚膜梭状芽孢杆菌硅糖苷酶能显著提高 MHC-I 的水平,这支持了一种观点,即更高的 MHC-I 水平是由于细胞表面蛋白上的特定硅糖被裂解所致。硅糖苷酶处理可在一小时内诱导 MHC-I、MHC-II 和 CD40 的表面表达迅速升高,这种反应在细胞因子鸡尾酒处理 48 小时后不能完全复制。硅糖苷酶处理 48 小时后也能观察到这些增加。CD86和PD-L1在细胞因子成熟48小时后显著增加,而在硅糖苷酶处理48小时后,CD86的增加幅度更大,PD-L1的增加幅度更短。硅糖苷酶处理 48 小时后,CCR-7 的表达明显增加,但细胞因子成熟对其影响不大。两种处理方法都能促进 IL-12 细胞因子的分泌。然而,鸡尾酒细胞因子诱导的IL-12分泌更为明显。SNA 凝集素染色分析表明,硅糖苷酶处理会显著改变硅糖酸谱,而细胞因子鸡尾酒则不会,因为后者只会导致硅糖酸轻微上调。值得注意的是,MoDCs 中的脂质呈递分子 CD1a、CD1b 和 CD1c 不受硅糖苷酶处理的影响,这一发现也得到了 C1R 细胞实验的进一步支持。在 MoDC 分化过程中抑制内源性硅糖苷酶 Neu1 和 Neu3 不会影响表面 MHC-I 的表达和细胞因子的分泌。然而,MoDC 中的硅糖苷酶活性极低,这表明硅糖苷酶抑制不会显著改变 MHC-I 相关功能。我们的研究强调了通过操纵硅酸诱导 MoDCs 成熟的独特特征。这些发现让我们了解到了操纵硅唾液酸作为一种快速免疫调节策略的潜力,为在炎症环境中进行有针对性的干预提供了前景广阔的途径。
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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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