Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
Laboratorio de Glicobiología y Biología Vascular, Instituto de Histología y Embriología de Mendoza, CONICET-Universidad Nacional de Cuyo, Mendoza, Argentina.
J Extracell Vesicles. 2023 Jun;12(6):e12331. doi: 10.1002/jev2.12331.
Although inflammation is a vital defence response to infection, if left uncontrolled, it can lead to pathology. Macrophages are critical players both in driving the inflammatory response and in the subsequent events required for restoring tissue homeostasis. Extracellular vesicles (EVs) are membrane-enclosed structures released by cells that mediate intercellular communication and are present in all biological fluids, including blood. Herein, we show that extracellular vesicles from plasma (pEVs) play a relevant role in the control of inflammation by counteracting PAMP-induced macrophage activation. Indeed, pEV-treatment of macrophages simultaneously with or prior to PAMP exposure reduced the secretion of pro-inflammatory IL-6 and TNF-α and increased IL-10 response. This anti-inflammatory activity was associated with the promotion of tissue-repair functions in macrophages, characterized by augmented efferocytosis and pro-angiogenic capacity, and increased expression of VEGFa, CD300e, RGS2 and CD93, genes involved in cell growth and tissue remodelling. We also show that simultaneous stimulation of macrophages with a PAMP and pEVs promoted COX2 expression and CREB phosphorylation as well as the accumulation of higher concentrations of PGE2 in cell culture supernatants. Remarkably, the anti-inflammatory activity of pEVs was abolished if cells were treated with a pharmacological inhibitor of COX2, indicating that pEV-mediated induction of COX2 is critical for the pEV-mediated inhibition of inflammation. Finally, we show that pEVs added to monocytes prior to their M-CSF-induced differentiation to macrophages increased efferocytosis and diminished pro-inflammatory cytokine responses to PAMP stimulation. In conclusion, our results suggest that pEVs are endogenous homeostatic modulators of macrophages, activating the PGE2/CREB pathway, decreasing the production of inflammatory cytokines and promoting tissue repair functions.
虽然炎症是对感染的重要防御反应，但如果不受控制，它可能导致病理学。巨噬细胞在驱动炎症反应和随后恢复组织内稳态所需的事件中都是关键参与者。细胞外囊泡（EVs）是由细胞释放的膜封闭结构，介导细胞间通讯，并存在于所有生物体液中，包括血液。本文中，我们表明，来自血浆的细胞外囊泡（pEVs）通过拮抗 PAMP 诱导的巨噬细胞激活，在炎症控制中发挥相关作用。事实上，pEV 处理巨噬细胞与 PAMP 暴露同时或之前，可减少促炎细胞因子 IL-6 和 TNF-α 的分泌，并增加 IL-10 反应。这种抗炎活性与巨噬细胞中组织修复功能的增强有关，其特征为吞噬作用和促血管生成能力增强，以及与细胞生长和组织重塑相关的基因 VEGFa、CD300e、RGS2 和 CD93 的表达增加。我们还表明，同时刺激巨噬细胞与 PAMP 和 pEVs 可促进 COX2 表达和 CREB 磷酸化，以及细胞培养上清液中 PGE2 浓度的升高。值得注意的是，如果用 COX2 的药理学抑制剂处理细胞，则 pEV 介导的 COX2 诱导被废除，这表明 pEV 介导的 COX2 诱导对于 pEV 介导的炎症抑制至关重要。最后，我们表明，在单核细胞分化为巨噬细胞之前，pEVs 可增加吞噬作用并减少对 PAMP 刺激的促炎细胞因子反应。总之，我们的结果表明，pEVs 是巨噬细胞的内源性稳态调节剂，激活 PGE2/CREB 途径，减少炎症细胞因子的产生，并促进组织修复功能。
