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巨噬细胞的昼夜节律被酸性肿瘤微环境改变。

Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.

机构信息

Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.

Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

出版信息

EMBO Rep. 2024 Nov;25(11):5080-5112. doi: 10.1038/s44319-024-00288-2. Epub 2024 Oct 16.

DOI:10.1038/s44319-024-00288-2
PMID:39415049
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11549407/
Abstract

Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.

摘要

肿瘤相关巨噬细胞（TAMs）因其促肿瘤生成功能而成为主要的治疗靶点，但靶向巨噬细胞的治疗效果各异，这突显了我们对巨噬细胞在肿瘤微环境（TME）中如何受到调控的理解还不完整。昼夜节律是巨噬细胞功能的关键调节剂，但 TME 如何影响巨噬细胞的昼夜节律仍不清楚。在这里，我们表明，与 TME 相关的条件，如极化刺激、酸性 pH 值和乳酸，可以改变巨噬细胞的昼夜节律。虽然环磷酸腺苷（cAMP）已被报道在巨噬细胞对酸性 pH 值的反应中发挥作用，但我们的结果表明，pH 值驱动的昼夜节律变化并非仅由 cAMP 信号介导。值得注意的是，通过时钟相关距离分析揭示了 TAMs 的昼夜节律紊乱。我们的数据表明，TAM 群体水平内昼夜节律的异质性可能是这种昼夜节律紊乱的基础。最后，我们报告说，巨噬细胞的昼夜节律调节抑制了胰腺癌小鼠模型中的肿瘤生长。我们的工作证明了 TME 通过调节昼夜节律来影响巨噬细胞生物学的一种新机制。

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IL-4 and IL-13: Regulators and Effectors of Wound Repair.
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Circadian disruption enhances HSF1 signaling and tumorigenesis in -driven lung cancer.生物钟紊乱增强了驱动的肺癌中的 HSF1 信号和肿瘤发生。
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The contribution of ion channels to shaping macrophage behaviour.离子通道对塑造巨噬细胞行为的作用。
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