Oxalate disrupts monocyte and macrophage cellular function via Interleukin-10 and mitochondrial reactive oxygen species (ROS) signaling.
Oxalate disrupts monocyte and macrophage cellular function via Interleukin-10 and mitochondrial reactive oxygen species (ROS) signaling.
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DOI：
10.1016/j.redox.2023.102919
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发表时间：
2023-11
期刊：
影响因子：
11.4
通讯作者：
Mitchell T
中科院分区：
文献类型：
--
作者：
Kumar P;Laurence E;Crossman DK;Assimos DG;Murphy MP;Mitchell T
草酸盐是在某些植物性食物中发现的一种小化合物，是草酸钙（CaOx）肾结石的主要成分。食用富含草酸盐的膳食的个体具有形成尿结晶的增加的风险，尿结晶是CaOx肾结石的前体。我们以前报道，一个单一的饮食草酸负荷诱导nanocomposia和减少单核细胞的细胞生物能量学在健康成年人。本研究的目的是扩展这些研究，以确定单核细胞和巨噬细胞中特定的尿酸盐介导的机制。我们对从暴露于高草酸盐（8 mmol）饮食负荷的健康受试者中分离的单核细胞进行RNA测序分析。RNA测序显示1，198个基因发生了改变，并且免疫途径分析证明了几种途径的修饰，包括白细胞介素-10（IL-10）抗炎细胞因子信号传导、线粒体代谢和功能、草酸下游信号传导和自噬。基于这些发现，我们假设草酸盐通过IL-10和活性氧（ROS）信号传导诱导单核细胞和巨噬细胞的线粒体和溶酶体功能障碍，而这可以用外源性IL-10或线粒体醌（MitoQ;线粒体靶向抗氧化剂）逆转。我们在体外环境中将单核细胞和巨噬细胞暴露于草酸盐，这导致氧化应激、IL-10细胞因子水平下降、线粒体和溶酶体功能障碍以及两种细胞类型中的自噬受损。外源性IL-10和MitoQ的施用减弱了这些应答。这些发现表明，草酸盐通过IL-10信号传导和单核细胞和巨噬细胞中的线粒体ROS产生损害代谢和免疫应答，这可能是有限的或逆转的。未来的研究将检查这些疗法对体内CaOx晶体形成和生长的益处。饮食草酸负荷改变健康受试者循环单核细胞的转录组学。草酸盐改变单核细胞和巨噬细胞中的白细胞介素-10（IL-10）和线粒体活性氧（ROS）水平。外源性白细胞介素-10（IL-10）和线粒体醌（MitoQ）治疗在体外逆转了尿酸盐介导的结果。食用富含草酸盐的食物会破坏单核细胞和巨噬细胞的代谢和免疫反应。
Oxalate is a small compound found in certain plant-derived foods and is a major component of calcium oxalate (CaOx) kidney stones. Individuals that consume oxalate enriched meals have an increased risk of forming urinary crystals, which are precursors to CaOx kidney stones. We previously reported that a single dietary oxalate load induces nanocrystalluria and reduces monocyte cellular bioenergetics in healthy adults. The purpose of this study was to extend these investigations to identify specific oxalate-mediated mechanisms in monocytes and macrophages. We performed RNA-Sequencing analysis on monocytes isolated from healthy subjects exposed to a high oxalate (8 mmol) dietary load. RNA-sequencing revealed 1,198 genes were altered and Ingenuity Pathway Analysis demonstrated modifications in several pathways including Interleukin-10 (IL-10) anti-inflammatory cytokine signaling, mitochondrial metabolism and function, oxalic acid downstream signaling, and autophagy. Based on these findings, we hypothesized that oxalate induces mitochondrial and lysosomal dysfunction in monocytes and macrophages via IL-10 and reactive oxygen species (ROS) signaling which can be reversed with exogenous IL-10 or Mitoquinone (MitoQ; a mitochondrial targeted antioxidant). We exposed monocytes and macrophages to oxalate in an in-vitro setting which caused oxidative stress, a decline in IL-10 cytokine levels, mitochondrial and lysosomal dysfunction, and impaired autophagy in both cell types. Administration of exogenous IL-10 and MitoQ attenuated these responses. These findings suggest that oxalate impairs metabolism and immune response via IL-10 signaling and mitochondrial ROS generation in both monocytes and macrophages which can be potentially limited or reversed. Future studies will examine the benefits of these therapies on CaOx crystal formation and growth in vivo. A dietary oxalate load alters transcriptomics in circulating monocytes from healthy subjects. Oxalate alters Interleukin-10 (IL-10) and mitochondrial reactive oxygen species (ROS) levels in monocytes and macrophages. Exogenous Interleukin-10 (IL-10) and Mitoquinone (MitoQ) treatment reverses oxalate-mediated outcomes in vitro. Consuming meals rich in oxalate could disrupt monocyte and macrophage metabolism and immune response.
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