磷酸肌醇-3-激酶 (PI3K)-delta 抑制剂 seletalisib 会损害单核细胞衍生的树突状细胞成熟、APC 功能，并促进它们向 CCR7 和 CXCR4 配体的迁移,Journal of Leukocyte Biology

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磷酸肌醇-3-激酶 (PI3K)-delta 抑制剂 seletalisib 会损害单核细胞衍生的树突状细胞成熟、APC 功能，并促进它们向 CCR7 和 CXCR4 配体的迁移
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2022-02-24 , DOI: 10.1002/jlb.1a0821-413rr
Fernanda Scopelliti ₁ , Laura Mercurio ₂ , Caterina Cattani ₁ , Valentina Dimartino ₁ , Cristina Albanesi ₂ , Gianfranco Costanzo ₁ , Concetta Mirisola ₁ , Stefania Madonna ₂ , Andrea Cavani ₁

Affiliation

PI3K 通路在树突状细胞 (DC) 功能中起着至关重要的作用，因为它调节不同的细胞过程，例如成熟和细胞因子的产生。然而，PI3K p110δ 异构体在人类 DCs 中的具体作用尚未得到彻底解决。在这项研究中，我们分析了 PI3K p110δ 的有效和特异性抑制剂 seletalisib 对通过 LPS 成熟的单核细胞衍生 DC 的表型和抗原呈递功能的影响。Seletalisib 治疗减少了膜 HLA-DR 以及 CD83 和 CD40 共刺激分子，而 CD80 和 CD86 表达仅部分受到影响。此外，DCs 培养物显示 TNF-α、IL-10 和 IL-12 减少，IL-23 分泌水平增加。这导致 DC 启动同种异体 T 细胞的能力降低，Th1 分化显着降低。另一方面，PI3K p110δ 抑制剂 seletalisib 增加了 CXCR4 和 CCR7 的表达，并增加了 DC 向 CCL19 和 CXCL12 配体的迁移。在分子水平上，seletalisib 对 PI3K p110δ 异构体的抑制显着下调了 AKT 和其他下游信号分子的磷酸化，例如核糖体蛋白 S6、4E-BP1 和 NF-κB p65。相反，seletalisib 不影响 DC 中的 p38 MAP 激酶磷酸化或 TLR 相关的衔接分子 TIRAP。我们的研究结果表明，PI3K p110δ 可以作为 DCs 的重要调节信号，而 seletalisib 对 PI3K p110δ 异构体的选择性抑制可用于预防病理条件下发生的过度和有害的免疫反应，例如自身免疫性疾病。

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The phosphoinositide-3-kinase (PI3K)-delta inhibitor seletalisib impairs monocyte-derived dendritic cells maturation, APC function, and promotes their migration to CCR7 and CXCR4 ligands

PI3K pathway plays a crucial role in dendritic cells (DCs) functions, as it regulates different cellular processes, such as maturation and cytokines production. However, the specific role of PI3K p110δ isoform in human DCs has not been thoroughly addressed. In this study, we analyze the effects of seletalisib, a potent and specific inhibitor of PI3K p110δ, on phenotype and antigen-presenting functions of monocyte-derived DCs undergone maturation via LPS. Seletalisib treatment reduced membrane HLA-DR as well as CD83 and CD40 costimulatory molecules, whereas CD80 and CD86 expression was only partially affected. Additionally, DCs cultures showed reduced TNF-α, IL-10, and IL-12 and increased IL-23 secretion levels. This resulted in a reduced capacity of DCs to prime allogeneic T cells, with a strong decrease of Th1 differentiation. On the other hand, PI3K p110δ inhibitor seletalisib increased CXCR4 and CCR7 expression and augmented the DCs migration toward CCL19 and CXCL12 ligands. At molecular level, inhibition of PI3K p110δ isoform by seletalisib significantly down-regulated the phosphorylation of AKT and other downstream signaling molecules, such as ribosomal protein S6, 4E-BP1, and NF-κB p65. In contrast, seletalisib did not affect p38 MAP kinase phosphorylation or TLR-associated adapter molecule TIRAP in DCs. Our results indicate that PI3K p110δ can serve as an important regulatory signal for DCs, and selective inhibition of PI3K p110δ isoform by seletalisib could be used for the prevention of exaggerated and harmful immune responses occurring in pathologic conditions, such as autoimmune disorders.

更新日期：2022-02-24

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