Spinster homolog 2/S1P signaling ameliorates macrophage inflammatory response to bacterial infections by balancing PGE2 production.

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Chao Fang, Pan Ren, Yejun He, Yitian Wang, Shuting Yao, Congying Zhao, Xueyong Li, Xi Zhang, Jinqing Li, Mingkai Li
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引用次数: 0

Abstract

Background: Mitochondria play a crucial role in shaping the macrophage inflammatory response during bacterial infections. Spinster homolog 2 (Spns2), responsible for sphingosine-1-phosphate (S1P) secretion, acts as a key regulator of mitochondrial dynamics in macrophages. However, the link between Spns2/S1P signaling and mitochondrial functions remains unclear.

Methods: Peritoneal macrophages were isolated from both wild-type and Spns2 knockout rats, followed by non-targeted metabolomics and RNA sequencing analysis to identify the potential mediators through which Spns2/S1P signaling influences the mitochondrial functions in macrophages. Various agonists and antagonists were used to modulate the activation of Spns2/S1P signaling and its downstream pathways, with the underlying mechanisms elucidated through western blotting. Mitochondrial functions were assessed using flow cytometry and oxygen consumption assays, as well as morphological analysis. The impact on inflammatory response was validated through both in vitro and in vivo sepsis models, with the specific role of macrophage-expressed Spns2 in sepsis evaluated using Spns2flox/floxLyz2-Cre mice. Additionally, the regulation of mitochondrial functions by Spns2/S1P signaling was confirmed using THP-1 cells, a human monocyte-derived macrophage model.

Results: In this study, we unveil prostaglandin E2 (PGE2) as a pivotal mediator involved in Spns2/S1P-mitochondrial communication. Spns2/S1P signaling suppresses PGE2 production to support malate-aspartate shuttle activity. Conversely, excessive PGE2 resulting from Spns2 deficiency impairs mitochondrial respiration, leading to intracellular lactate accumulation and increased reactive oxygen species (ROS) generation through E-type prostanoid receptor 4 activation. The overactive lactate-ROS axis contributes to the early-phase hyperinflammation during infections. Prolonged exposure to elevated PGE2 due to Spns2 deficiency culminates in subsequent immunosuppression, underscoring the dual roles of PGE2 in inflammation throughout infections. The regulation of PGE2 production by Spns2/S1P signaling appears to depend on the coordinated activation of multiple S1P receptors rather than any single one.

Conclusions: These findings emphasize PGE2 as a key effector of Spns2/S1P signaling on mitochondrial dynamics in macrophages, elucidating the mechanisms through which Spns2/S1P signaling balances both early hyperinflammation and subsequent immunosuppression during bacterial infections.

Spinster homolog 2/S1P 信号通过平衡 PGE2 的产生来改善巨噬细胞对细菌感染的炎症反应。
背景:线粒体在细菌感染期间对巨噬细胞炎症反应的形成起着至关重要的作用。负责鞘氨醇-1-磷酸(S1P)分泌的 Spinster homolog 2(Spns2)是巨噬细胞线粒体动力学的关键调节因子。然而,Spns2/S1P 信号传导与线粒体功能之间的联系仍不清楚:方法:从野生型大鼠和 Spns2 基因敲除大鼠体内分离腹腔巨噬细胞,然后进行非靶向代谢组学和 RNA 测序分析,以确定 Spns2/S1P 信号转导影响巨噬细胞线粒体功能的潜在介质。研究人员使用了各种激动剂和拮抗剂来调节 Spns2/S1P 信号的激活及其下游通路,并通过 Western 印迹分析阐明了其潜在机制。通过流式细胞术和耗氧量测定以及形态学分析评估线粒体功能。通过体外和体内败血症模型验证了 Spns2 对炎症反应的影响,并利用 Spns2flox/floxLyz2-Cre 小鼠评估了巨噬细胞表达的 Spns2 在败血症中的特殊作用。此外,使用 THP-1 细胞(一种源自人类单核巨噬细胞的模型)证实了 Spns2/S1P 信号对线粒体功能的调节作用:结果:在这项研究中,我们发现前列腺素 E2(PGE2)是参与 Spns2/S1P 与线粒体交流的关键介质。Spns2/S1P 信号抑制 PGE2 的产生,以支持苹果酸-天门冬氨酸穿梭活动。相反,Spns2 缺乏导致的过量 PGE2 会损害线粒体呼吸,从而导致细胞内乳酸积聚,并通过 E 型前列腺素受体 4 的激活增加活性氧(ROS)的生成。乳酸-ROS 轴的过度活跃导致了感染早期的高炎症反应。由于缺乏 Spns2,长期暴露于升高的 PGE2 会导致随后的免疫抑制,这突出表明了 PGE2 在整个感染过程中对炎症的双重作用。Spns2/S1P 信号对 PGE2 生成的调控似乎取决于多个 S1P 受体的协调激活,而不是任何单一受体:这些发现强调了 PGE2 是 Spns2/S1P 信号对巨噬细胞线粒体动力学的关键效应因子,阐明了 Spns2/S1P 信号在细菌感染期间平衡早期过度炎症和随后免疫抑制的机制。
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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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