Pro-inflammatory cytokines and leukocyte integrins associated with chronic neuropathic pain in traumatic and inflammatory neuropathies: Initial observations and hypotheses.
Pro-inflammatory cytokines and leukocyte integrins associated with chronic neuropathic pain in traumatic and inflammatory neuropathies: Initial observations and hypotheses.
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DOI：
10.3389/fimmu.2022.935306
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
周围神经内的白细胞浸润和持续存在与小鼠周围神经病模型的慢性伤害感受发病机制有关。神经内细胞因子和趋化因子的表达有助于白细胞浸润和维持促炎状态，从而延迟周围神经恢复并促进这些小鼠的慢性疼痛行为。然而，一直未能将小鼠模型数据转化为周围神经病患者慢性神经病理性疼痛的安全有效的治疗方法，也未能开发出有助于诊断或确定受影响患者治疗反应的可靠生物标志物。初步研究表明，在三种炎症和创伤性周围神经病小鼠模型中，持续性坐骨神经 CD11b+ CD45+ 白细胞浸润与疾病严重程度相关，这意味着在疾病发病机制中具有直接贡献作用。为了支持这一点，在患有三种不同周围神经病的慢性神经性疼痛患者的腓肠神经活检中也发现了 CD11b+ 白细胞。使用经过验证的功能中和单克隆抗体进行全身性 CD11b 拮抗可有效治疗单侧坐骨神经挤压损伤（与轴突变性和血神经屏障通透性增加相关的代表性创伤性神经病模型）后的慢性伤害感受，并且不会引起成年小鼠的药物成瘾行为。这些数据表明 CD11b 可能是治疗炎症和创伤性周围神经病慢性神经病理性疼痛的有效分子靶点。尽管已知小鼠周围神经病变模型的局限性，我们的初步工作表明促炎细胞因子的早期表达，例如金属蛋白酶-1的组织抑制剂，可以预测单侧坐骨神经挤压损伤后随后的慢性伤害感受的发展。将动物模型研究与充分表征的人类周围神经病变的观察数据相结合的研究，包括转录组学和蛋白质组学，以及使用人类临床试验设计的动物模型研究，应促进识别临床相关生物标志物和有效的靶向治疗，对周围神经病变患者的慢性神经病理性疼痛具有有限的成瘾潜力。
Leukocyte infiltration and persistence within peripheral nerves have been implicated in chronic nociception pathogenesis in murine peripheral neuropathy models. Endoneurial cytokine and chemokine expression contribute to leukocyte infiltration and maintenance of a pro-inflammatory state that delays peripheral nerve recovery and promotes chronic pain behaviors in these mice. However, there has been a failure to translate murine model data into safe and effective treatments for chronic neuropathic pain in peripheral neuropathy patients, or develop reliable biomarkers that may help diagnose or determine treatment responses in affected patients. Initial work showed that persistent sciatic nerve CD11b+ CD45+ leukocyte infiltration was associated with disease severity in three mouse models of inflammatory and traumatic peripheral neuropathies, implying a direct contributing role in disease pathogenesis. In support of this, CD11b+ leukocytes were also seen in the sural nerve biopsies of chronic neuropathic pain patients with three different peripheral neuropathies. Systemic CD11b antagonism using a validated function-neutralizing monoclonal antibody effectively treated chronic nociception following unilateral sciatic nerve crush injury (a representative traumatic neuropathy model associated with axonal degeneration and increased blood-nerve barrier permeability) and does not cause drug addiction behaviors in adult mice. These data suggest that CD11b could be an effective molecular target for chronic neuropathic pain treatment in inflammatory and traumatic peripheral neuropathies. Despite known murine peripheral neuropathy model limitations, our initial work suggests that early expression of pro-inflammatory cytokines, such as tissue inhibitor of metalloproteinases-1 may predict subsequent chronic nociception development following unilateral sciatic nerve crush injury. Studies aligning animal model investigation with observational data from well-characterized human peripheral neuropathies, including transcriptomics and proteomics, as well as animal model studies using a human clinical trial design should foster the identification of clinically relevant biomarkers and effective targeted treatments with limited addiction potential for chronic neuropathic pain in peripheral neuropathy patients.
DOI：
10.1111/j.1529-8027.2012.00375.x
发表时间：
2012-03
期刊：
Journal of the peripheral nervous system : JPNS
影响因子：
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作者：
Ubogu EE;Yosef N;Xia RH;Sheikh KA
通讯作者：
Sheikh KA