Picco Francesca, Zeboudj Lynda, Oggero Silvia, Prato Vincenzo, Burgoyne Thomas, Gamper Nikita, Malcangio Marzia
Wolfson Sensory, Pain and Regeneration Centre, King's College London, London, United Kingdom.
Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom.
Heliyon. 2024 Dec 17;11(1):e41268. doi: 10.1016/j.heliyon.2024.e41268. eCollection 2025 Jan 15.
Neuropathic pain following peripheral nerve injury results from maladaptive changes in neurons and immune cells contribution to mechanisms underlying chronic pain. Specifically, in dorsal root ganglia (DRG), sensory neuron cell bodies release extracellular vesicles (EVs) which promote pro-inflammatory macrophage accumulation that facilitates nociceptive signalling. Here, we show that macrophages shuttle EVs to neurons. Indeed, bone marrow-derived macrophages (BMDMs) release EVs containing microRNA-155 (miR-155) which are taken up by cultured sensory neurons. EV-mediated transfer of miR-155 suppresses phosphatase expression and increases cytokine interleukin-6 (IL-6) contents. Intrathecal-injected BMDM-derived EVs accumulate in lumbar DRG and EVs containing miR-155 antagomir result in upregulation, downregulation in neurons in concomitance to attenuation of neuropathic mechanical hypersensitivity. These data suggest that, under neuropathic conditions, pro-inflammatory macrophages shuttle EV-containing miR-155 to neurons and contribute to the expression of pronociceptive IL-6 in DRG.
外周神经损伤后的神经性疼痛源于神经元的适应性变化以及免疫细胞对慢性疼痛潜在机制的作用。具体而言，在背根神经节（DRG）中，感觉神经元细胞体会释放细胞外囊泡（EVs），这些囊泡会促进促炎性巨噬细胞的积累，从而促进伤害性信号传导。在此，我们表明巨噬细胞会将EVs转运至神经元。实际上，骨髓来源的巨噬细胞（BMDMs）会释放含有微小RNA-155（miR-155）的EVs，这些EVs会被培养的感觉神经元摄取。EV介导的miR-155转移会抑制磷酸酶的表达并增加细胞因子白细胞介素-6（IL-6）的含量。鞘内注射的BMDM来源的EVs会在腰段DRG中积累，而含有miR-155拮抗剂的EVs会导致神经元中相关蛋白上调、下调，同时伴有神经性机械性超敏反应的减弱。这些数据表明，在神经性疼痛状态下，促炎性巨噬细胞会将含有miR-155的EVs转运至神经元，并促进DRG中伤害性IL-6的表达。
