Liu Yun, Sun Xiao, Jia Zhengxu, Hou Qun, Yuan Mingqian, Xu Tiancheng, Yuan Jinhong, Xu Bin, Yu Zhi
Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China.
Purinergic Signal. 2025 Apr 28. doi: 10.1007/s11302-025-10088-5.
Hyperactivation of cutaneous macrophages promotes the development of chronic pain. Stimulation of nociceptive regions promotes neuroplasticity, which affects pain perception and related physiological responses. However, the specific mechanisms by which cutaneous macrophages sense and elicit nociceptive responses are unknown. Here, we exacerbated the reduction of systemic pain threshold after chronic heart failure (CHF) by silencing follistatin-like 1 (FSTL1), especially the abnormal cutaneous nociceptive sensation at PC6 acupoint, the site associated with cardiac involvement pain. The upregulation of P2Y6 and interleukin-27 expression is intimately linked to the activation of skin macrophages. Hyperactivation of P2Y6 receptor (P2Y6R) may be associated with MHC II M1 macrophage polarization in PC6. Thus, P2Y6 is one of the key factors that modulate the functional polarization of skin macrophages, which may subsequently influence the expansion of the pain field. The supportive effect of CD206 M2 macrophages on the cutaneous FSTL1 nerves was significantly reduced. Meanwhile, FSTL1 nerves in PC6 functionally interacted with calcitonin gene-related peptide (CGRP) nerves, and the overactivation of nerve growth factor (NGF) secreted by cutaneous macrophages induced CGRP neuropathological remodeling, which supported the enlargement of the pain sensory area. The activation of CGRP and P2X3 receptor (P2X3R), Na/K ATPase (NKA), and P2X3R in the C8 DRG may be one of the molecular bases mediating cutaneous nociceptive transmission and affecting the function of the heart. Hyperactivation of NKA was consistent with decreased pain threshold and changes in cardiac dysfunction, and PC6 injection of an NKA inhibitor (digilanid C) was effective in ameliorating nociception and cardiac impairment. The beneficial effects of digilanid C were counteracted by FSTL1 silencing. These results indicated that P2Y6 mediates the remodeling of pain perception by skin macrophages via the action of FSTL1, while NKA inhibitors synergistically exert their therapeutic effects.
皮肤巨噬细胞的过度激活促进慢性疼痛的发展。伤害性感受区域的刺激促进神经可塑性，这会影响疼痛感知和相关的生理反应。然而，皮肤巨噬细胞感知并引发伤害性反应的具体机制尚不清楚。在此，我们通过沉默卵泡抑素样蛋白1（FSTL1）加剧了慢性心力衰竭（CHF）后全身疼痛阈值的降低，尤其是PC6穴位处异常的皮肤伤害性感觉，该穴位与心脏牵涉痛相关。P2Y6和白细胞介素-27表达的上调与皮肤巨噬细胞的激活密切相关。P2Y6受体（P2Y6R）的过度激活可能与PC6中MHC II M1巨噬细胞极化有关。因此，P2Y6是调节皮肤巨噬细胞功能极化的关键因素之一，这可能随后影响疼痛区域的扩大。CD206 M2巨噬细胞对皮肤FSTL1神经的支持作用显著降低。同时，PC6中的FSTL1神经与降钙素基因相关肽（CGRP）神经在功能上相互作用，皮肤巨噬细胞分泌的神经生长因子（NGF）的过度激活诱导CGRP神经病理重塑，这支持了疼痛感觉区域的扩大。C8背根神经节中CGRP和P2X3受体（P2X3R）、钠钾ATP酶（NKA）以及P2X3R的激活可能是介导皮肤伤害性传递并影响心脏功能的分子基础之一。NKA的过度激活与疼痛阈值降低和心脏功能障碍的变化一致，PC6注射NKA抑制剂（毛花苷C）可有效改善伤害性感受和心脏损伤。毛花苷C的有益作用被FSTL1沉默抵消。这些结果表明，P2Y6通过FSTL1的作用介导皮肤巨噬细胞对疼痛感知的重塑，而NKA抑制剂协同发挥其治疗作用。
