Excess Potassium Promotes Autophagy to Maintain the Immunosuppressive Capacity of Myeloid-Derived Suppressor Cells Independent of Arginase 1.

IF 5.1 2区 生物学 Q2 CELL BIOLOGY
Cells Pub Date : 2024-10-19 DOI:10.3390/cells13201736
Ramesh Thylur Puttalingaiah, Matthew J Dean, Liqin Zheng, Phaethon Philbrook, Dorota Wyczechowska, Timothy Kayes, Luis Del Valle, Denise Danos, Maria Dulfary Sanchez-Pino
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引用次数: 0

Abstract

Potassium ions (K+) are critical electrolytes that regulate multiple functions in immune cells. Recent studies have shown that the elevated concentration of extracellular potassium in the tumor interstitial fluid limits T cell effector function and suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). The effect of excess potassium on the biology of myeloid-derived suppressor cells (MDSCs), another important immune cell component of the tumor microenvironment (TME), is unknown. Here, we present data showing that increased concentrations of potassium chloride (KCl), as the source of K+ ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3β. Simultaneously, excess potassium ions significantly decrease the expression of arginase I (Arg I) and inducible nitric oxide synthase (iNOS) without reducing the ability of MDSCs to suppress T cell proliferation. Further investigation reveals that excess K+ ions decrease the expression of the transcription factor C/EBP-β and alter the expression of phosphorylated kinases. While excess K+ ions downregulated the expression levels of phospho-AMPKα (pAMPKα), it increased the levels of pAKT and pERK. Additionally, potassium increased mitochondrial respiration as measured by the oxygen consumption rate (OCR). Interestingly, all these alterations induced by K+ ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K+ ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs' immunosuppressive function by mechanisms independent of Arg I and iNOS. Overall, our in vitro and ex vivo findings offer valuable insights into the adaptations of MDSCs within the K+ ion-rich TME, which has important implications for MDSCs-targeted therapies.

过量的钾促进自噬以维持髓系衍生抑制细胞的免疫抑制能力,而不依赖于精氨酸酶 1。
钾离子(K+)是调节免疫细胞多种功能的重要电解质。最近的研究表明,肿瘤间质液中细胞外钾浓度升高会限制 T 细胞效应功能,并抑制肿瘤相关巨噬细胞(TAMs)的抗肿瘤能力。过量的钾对肿瘤微环境(TME)中另一种重要的免疫细胞成分--髓源性抑制细胞(MDSCs)的生物学影响尚不清楚。在此,我们提供的数据显示,氯化钾(KCl)作为 K+ 离子的来源,其浓度的增加会通过增加自噬体标记物 LC3β 的表达来促进自噬。同时,过量的钾离子会显著降低精氨酸酶 I(Arg I)和诱导型一氧化氮合酶(iNOS)的表达,而不会降低 MDSCs 抑制 T 细胞增殖的能力。进一步研究发现,过量的 K+ 离子会降低转录因子 C/EBP-β 的表达,并改变磷酸化激酶的表达。虽然过量的 K+ 离子会降低磷酸-AMPKα(pAMPKα)的表达水平,但会增加 pAKT 和 pERK 的表达水平。此外,通过耗氧率(OCR)测量,钾增加了线粒体呼吸。有趣的是,自噬抑制剂 3-甲基腺嘌呤(3-MA)可消除 K+ 离子诱导的所有这些变化。我们的研究结果表明,过量 K+ 离子引起的高渗应激通过独立于 Arg I 和 iNOS 的机制调节 MDSCs 的线粒体呼吸和信号通路,从而触发自噬过程,支持 MDSCs 的免疫抑制功能。总之,我们的体外和体内研究结果为了解 MDSCs 在富含 K+ 离子的 TME 中的适应性提供了有价值的见解,这对 MDSCs 靶向疗法具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cells
Cells Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
9.90
自引率
5.00%
发文量
3472
审稿时长
16 days
期刊介绍: Cells (ISSN 2073-4409) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to cell biology, molecular biology and biophysics. It publishes reviews, research articles, communications and technical notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided.
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