Intercellular communications are important for maintaining normal physiological processes. An important intercellular communication is mediated by the exchange of membrane-enclosed extracellular vesicles. Among various vesicles, exosomes can be detected in a wide variety of biological systems, but the regulation and biological implication of exosome secretion/uptake remains largely unclear. Cellular retinoic acid (RA) binding protein 1 (Crabp1) knockout (CKO) mice were used for in vivo studies. Extracellular exosomes were monitored in CKO mice and relevant cell cultures including embryonic stem cell (CJ7), macrophage (Raw 264.7) and hippocampal cell (HT22) using Western blot and flow cytometry. Receptor Interacting Protein 140 (RIP140) was depleted by Crispr/Cas9-mediated gene editing. Anti-inflammatory maker was analyzed using qRT-PCR. Clinical relevance was accessed by mining multiple clinical datasets. This study uncovers Crabp1 as a negative regulator of exosome secretion from neurons. Specifically, RIP140, a pro-inflammatory regulator, can be transferred from neurons, via Crabp1-regulated exosome secretion, into macrophages to promote their inflammatory polarization. Consistently, CKO mice, defected in the negative control of exosome secretion, have significantly elevated RIP140-containing exosomes in their blood and cerebrospinal fluid, and exhibit an increased vulnerability to systemic inflammation. Clinical relevance of this pathway is supported by patients’ data of multiple inflammatory diseases. Further, the action of Crabp1 in regulating exosome secretion involves its ligand and is mediated by its downstream target, the MAPK signaling pathway. This study presents the first evidence for the regulation of exosome secretion, which mediates intercellular communication, by RA-Crabp1 signaling. This novel mechanism can contribute to the control of systemic inflammation by transferring an inflammatory regulator, RIP140, between cells. This represents a new mechanism of vitamin A action that can modulate the homeostasis of system-wide innate immunity without involving gene regulation.

中文翻译：

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细胞视黄酸结合蛋白 1 对外泌体分泌的调节有助于全身抗炎

细胞间通讯对于维持正常的生理过程很重要。一种重要的细胞间通讯是由膜包裹的细胞外囊泡的交换介导的。在各种囊泡中，外泌体可以在多种生物系统中检测到，但外泌体分泌/摄取的调控和生物学意义仍不清楚。细胞维甲酸 (RA) 结合蛋白 1 (Crabp1) 敲除 (CKO) 小鼠用于体内研究。使用蛋白质印迹和流式细胞术在 CKO 小鼠和相关细胞培养物中监测细胞外外泌体，包括胚胎干细胞 (CJ7)、巨噬细胞 (Raw 264.7) 和海马细胞 (HT22)。受体相互作用蛋白 140 (RIP140) 被 Crispr/Cas9 介导的基因编辑耗尽。使用 qRT-PCR 分析抗炎标志物。通过挖掘多个临床数据集来访问临床相关性。这项研究揭示了 Crabp1 作为神经元外泌体分泌的负调节因子。具体来说，促炎调节剂 RIP140 可以通过 Crabp1 调节的外泌体分泌从神经元转移到巨噬细胞中，以促进其炎症极化。一致地，在外泌体分泌负控制方面有缺陷的 CKO 小鼠在其血液和脑脊液中显着升高了含有 RIP140 的外泌体，并且表现出对全身炎症的易感性增加。患者的多种炎症性疾病数据支持该途径的临床相关性。此外，Crabp1 在调节外泌体分泌中的作用涉及其配体，并由其下游靶标 MAPK 信号通路介导。这项研究提供了通过 RA-Crabp1 信号传导调节外泌体分泌的第一个证据，外泌体分泌介导细胞间通讯。这种新机制可以通过在细胞之间转移炎症调节因子 RIP140 来帮助控制全身炎症。这代表了一种新的维生素 A 作用机制，可以在不涉及基因调控的情况下调节全系统先天免疫的稳态。