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IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine Pub Date : 2024-12-18 DOI:10.1016/j.cyto.2024.156831

Joni Yadav, Tanya Tripathi, Apoorva Chaudhary, Divya Janjua, Udit Joshi, Nikita Aggarwal, Arun Chhokar, Chetkar Chandra Keshavam, Anna Senrung, Alok Chandra Bharti

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引用次数: 0

摘要

背景：肿瘤微环境（TME）中的肿瘤细胞会释放影响巨噬细胞表型的外泌体，这些外泌体或具有促致癌作用，或具有抗致癌作用。人们对这一机制，尤其是头颈部鳞状细胞癌（HNSCC）的这一机制仍知之甚少。本研究探讨了HNSCC外泌体在巨噬细胞极化中的作用：方法：从HPV16阳性（93VU147T、UDSCC2）和HPV阴性（OCT1）的HNSCC细胞系中分离出外泌体。这些外泌体具有调节巨噬细胞极化的潜力。通过共聚焦显微镜监测巨噬细胞对外泌体PKH-26标记的摄取。使用定量实时 PCR 和免疫印迹法评估巨噬细胞极化的变化。外泌体转录本和蛋白质组货物用于检测极化相关介质：结果：HPV阴性外泌体显示出更高的THP1静息巨噬细胞（M0）吸收率。HPV阳性细胞的外泌体诱导了混合巨噬细胞表型（M1和M2），而HPV阴性外泌体则有利于M1极化。免疫印迹分析表明，这种极化是由转录因子 STAT1、NF-κB 和 AP1 的激活驱动的。HNSCC外泌体的转录组分析显示了AP1（c-Jun、c-Fos、FosB、Fra1、Fra2）和NF-κB（p50/105、p52/100、RelA、RelB、c-Rel）以及它们已知的上游介质MEK1--7、JNK1-3、JAK1-3、TYK2、IKKα和IKKβ的读数。此外，还发现了巨噬细胞极化标志物的剪接变体，包括iNOS和TGFβ，但没有一种外泌体蛋白质组成分与这些因子相对应：结论：HPV阴性外泌体可被巨噬细胞有效内化，可能通过调节STAT1、NF-κB和AP1信号促进M1极化。这些发现为了解肿瘤外泌体在 HNSCC 中巨噬细胞介导的 TME 动态调节中的作用提供了新的视角。

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Influence of head and neck cancer exosomes on macrophage polarization.

Background: Tumor cells within the tumor microenvironment (TME) release exosomes that influence macrophage phenotypes, either pro-tumorigenic or anti-tumorigenic. This mechanism, especially in head and neck squamous cell carcinoma (HNSCC), remains poorly understood. This study investigates the role of HNSCC exosomes in macrophage polarization.

Methodology: Exosomes were isolated from HPV16-positive (93VU147T, UDSCC2) and HPV-negative (OCT1) HNSCC cell lines. These exosomes were characterized for their potential to modulate macrophage polarization. Uptake of PKH-26 labeled exosomes by macrophages was monitored via confocal microscopy. Changes in macrophage polarization were assessed using quantitative real-time PCR and immunoblotting. Exosomal transcripts and proteome cargo was examined for polarization associated mediators.

Results: HPV-negative exosomes showed higher uptake by THP1 resting macrophages (M0). Exosomes from HPV-positive cells induced a mixed macrophage phenotype (M1 and M2), whereas HPV-negative exosomes favored M1 polarization. Immunoblotting analysis revealed that this polarization was driven by the activation of transcription factors STAT1, NF-κB, and AP1. Transcriptomic analysis of HNSCC exosomes revealed reads for AP1 (c-Jun, c-Fos, FosB, Fra1, Fra2) and NF-κB (p50/105, p52/100, RelA, RelB, c-Rel), along with their known upstream mediators MEK1--7, JNK1-3, JAK1-3, TYK2, IKKα, and IKKβ. Splice variants of macrophage polarization markers, including iNOS and TGFβ, were also identified, though none of the exosomal proteome component corresponded to these factors.

Conclusion: HPV-negative exosomes are efficiently internalized by macrophages, promoting M1 polarization likely via modulation of STAT1, NF-κB, and AP1 signaling. These findings provide novel insights into role of tumor exosomes in modulation of macrophage-mediated TME dynamics in HNSCC.

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来源期刊

Cytokine 医学-免疫学

CiteScore

7.60

自引率

2.60%

发文量

262

审稿时长

48 days

期刊介绍： The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. * Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors. We will publish 3 major types of manuscripts: 1) Original manuscripts describing research results. 2) Basic and clinical reviews describing cytokine actions and regulation. 3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.