Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain
Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain
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DOI：
10.1073/pnas.0610811104
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发表时间：
2007-06-19
影响因子：
11.1
通讯作者：
Malcangio, Marzia
中科院分区：
文献类型：
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作者：
Clark, Anna K.;Yip, Ping K.;Malcangio, Marzia
最近的一个主要概念进展是认识到免疫系统-神经元相互作用在脑功能调节中的重要性，其中一个例子是神经病理状态下的脊髓疼痛处理。在这里，我们报告说，在周围神经损伤的大鼠，溶酶体半胱氨酸蛋白酶组织蛋白酶S（CatS）是维持神经病理性疼痛和脊髓小胶质细胞活化的关键。损伤后，CatS仅由同侧背角中的活化小胶质细胞表达，其中表达在第7天达到峰值，在第14天保持高水平。鞘内递送不可逆CatS抑制剂，吗啉脲-亮氨酸-高苯丙氨酸-乙烯基苯砜（LHVS），在神经病大鼠中具有抗痛觉过敏和抗异常性疼痛作用，并减弱脊髓小胶质细胞活化。与内源性CatS的原伤害感受作用一致，大鼠重组CatS（rrCatS）的脊髓鞘内递送在幼稚大鼠中诱导痛觉过敏和异常性疼痛，并在脊髓小胶质细胞中激活p38丝裂原活化蛋白激酶（MAPK）。生物信息学方法揭示了跨膜趋化因子fractalkine（FKN）是CatS切割的潜在底物。我们发现，rrCatS孵育降低了培养的感觉神经元中细胞相关FKN的水平，并且针对FKN的中和抗体防止了FKN和CatS诱导的异常性疼痛、痛觉过敏和p38 MAPK激活。此外，rrCatS诱导异常性疼痛的野生型，但不CX 3CR 1敲除小鼠。我们认为，在增加伤害感受的条件下，小胶质细胞CatS负责释放神经元FKN，其刺激小胶质细胞中的p38 MAPK磷酸化，从而通过释放原伤害感受介质激活神经元。
A recent major conceptual advance has been the recognition of the importance of immune system-neuronal interactions in the modulation of brain function, one example of which is spinal pain processing in neuropathic states. Here, we report that in peripheral nerve-injured rats, the lysosomal cysteine protease cathepsin S (CatS) is critical for the maintenance of neuropathic pain and spinal microglia activation. After injury, CatS was exclusively expressed by activated microglia in the ipsilateral dorsal horn, where expression peaked at day 7, remaining high on day 14. Intrathecal delivery of an irreversible CatS inhibitor, morpholinurea-leucine-homophenylalanine-vinyl phenyl sulfone (LHVS), was antihyperalgesic and antiallodynic in neuropathic rats and attenuated spinal microglia activation. Consistent with a pronociceptive role of endogenous CatS, spinal intrathecal delivery of rat recombinant CatS (rrCatS) induced hyperalgesia and allodynia in naive rats and activated p38 mitogen-activated protein kinase (MAPK) in spinal cord microglia. A bioinformatics approach revealed that the transmembrane chemokine fractalkine (FKN) is a potential substrate for CatS cleavage. We show that rrCatS incubation reduced the levels of cell-associated FKN in cultured sensory neurons and that a neutralizing antibody against FKN prevented both FKN- and CatS-induced allodynia, hyperalgesia, and p38 MAPK activation. Furthermore, rrCatS induced allodynia in wild-type but not CX3CR1-knockout mice. We suggest that under conditions of increased nociception, microglial CatS is responsible for the liberation of neuronal FKN, which stimulates p38 MAPK phosphorylation in microglia, thereby activating neurons via the release of pronociceptive mediators.