Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation
Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation
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DOI：
10.1073/pnas.0903524106
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发表时间：
2009-08-04
影响因子：
11.1
通讯作者：
Kishioka, Shiroh
中科院分区：
文献类型：
--
作者：
Maeda, Takehiko;Kiguchi, Norikazu;Kishioka, Shiroh
神经损伤可能导致神经病理性疼痛，其特征是痛觉过敏和痛觉过敏。越来越多的证据表明，神经病理性疼痛存在由神经元、胶质细胞和免疫细胞产生的分子底物。在这里，我们证明了瘦素，一种由脂肪细胞产生的脂肪因子，在部分坐骨神经结扎(PSL)小鼠通过巨噬细胞激活而发生触觉过敏的过程中起着关键作用。PSL可增加损伤坐骨神经(SCN)外膜脂肪细胞中瘦素的表达。瘦素缺乏的动物ob/ob小鼠没有表现出PSL诱导的触觉超敏，这种情况可以通过向受损的SCN注射瘦素来逆转。神经周围注射抗瘦素的中和抗体重现了这种衰减。被招募到SCN神经束膜的巨噬细胞表达瘦素受体和磷酸化信号转导和转录激活因子3(PSTAT3)，这是瘦素下游的转录因子。PSL还上调了损伤的SCN中可接受的神经病理性疼痛介质--环氧合酶-2、诱导型一氧化氮合酶和基质金属蛋白酶-9，并通过pSTAT3转录激活了它们的基因启动子。这种上调在用瘦素处理的巨噬细胞系中部分复制。将瘦素处理的腹膜巨噬细胞注射到受损的SCN，逆转了ob/ob小鼠出现PSL诱导的触觉过敏的失败。我们认为，瘦素诱导募集的巨噬细胞产生伤害感受性介质，从而促进触觉异常痛觉的发生。这份报告表明，与初级传入神经元相关的脂肪细胞可能通过分泌脂肪因子参与神经病理性疼痛的发生。
Nerve injury may result in neuropathic pain, characterized by allodynia and hyperalgesia. Accumulating evidence suggests the existence of a molecular substrate for neuropathic pain produced by neurons, glia, and immune cells. Here, we show that leptin, an adipokine exclusively produced by adipocytes, is critical for the development of tactile allodynia through macrophage activation in mice with partial sciatic nerve ligation (PSL). PSL increased leptin expression in adipocytes distributed at the epineurium of the injured sciatic nerve (SCN). Leptin-deficient animals, ob/ob mice, showed an absence of PSL-induced tactile allodynia, which was reversed by the administration of leptin to the injured SCN. Perineural injection of a neutralizing antibody against leptin reproduced this attenuation. Macrophages recruited to the perineurium of the SCN expressed the leptin receptor and phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a transcription factor downstream of leptin. PSL also up-regulated the accepted mediators of neuropathic pain-namely, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloprotease-9-in the injured SCN, with transcriptional activation of their gene promoters by pSTAT3. This up-regulation was partly reproduced in a macrophage cell line treated with leptin. Administration of peritoneal macrophages treated with leptin to the injured SCN reversed the failure of ob/ob mice to develop PSL-induced tactile allodynia. We suggest that leptin induces recruited macrophages to produce pronociceptive mediators for the development of tactile allodynia. This report shows that adipocytes associated with primary afferent neurons may be involved in the development of neuropathic pain through adipokine secretion.