Kang Dong Ho, Kim Woong Mo, Bae Hong Beom, Yang Jihoon, Choi Jeong Il
Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Gwangju, South Korea.
Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea.
Heliyon. 2024 Nov 28;10(24):e40694. doi: 10.1016/j.heliyon.2024.e40694. eCollection 2024 Dec 30.
Macrophage-inducible C-type lectin (Mincle) has emerged as a potential contributor to neuropathic pain induction and neuroinflammatory responses within the spinal cord. Moreover, evidence suggests a close association between toll-like receptor (TLR) and Mincle expression in myeloid cells. This study evaluated the effectiveness of Mincle antibodies in neuropathic pain and identified the epitope of these antibodies. In addition, the mode of interaction between Mincle and TLR inhibition was explored using isobolographic analysis.
Three different Mincle antibodies and a specific TLR4 inhibitor (TAK-242) were intrathecally administered, and mechanical allodynia was evaluated using the von Frey test in a rat model of spinal nerve ligation (SNL). Isobolographic analysis was conducted on the effect of combination of TAK-242 and Mincle Ab. Microarray analysis examined the specific region of Mincle targeted by the antibodies.
All Mincle antibodies and TAK-242 significantly alleviated mechanical allodynia in a dose-dependent manner. However, the maximal possible effects (MPE) produced by the antibodies ranged widely from 37.1 % to 91.8 %, comparable to that of TAK-242 (88.7 %). The combination of TAK-242 and the antibody with the highest MPE resulted in an additive interaction for their anti-allodynic effects. Epitope mapping revealed that each antibody targeted the extracellular domain, with epitope lengths ranging from 5 to 15 amino acids.
The current study demonstrates the anti-allodynic effect of Mincle antibodies and additive interaction with TLR4 inhibition in spinal nerve ligation model, suggesting the potential of blocking of Mincle signaling with its antibodies as a novel treatment strategy for neuropathic pain.
巨噬细胞诱导性C型凝集素（Mincle）已成为神经性疼痛诱导和脊髓内神经炎症反应的潜在促成因素。此外，有证据表明髓样细胞中Toll样受体（TLR）与Mincle表达之间存在密切关联。本研究评估了Mincle抗体在神经性疼痛中的有效性，并确定了这些抗体的表位。此外，使用等效线图分析探讨了Mincle与TLR抑制之间的相互作用模式。
鞘内注射三种不同的Mincle抗体和一种特异性TLR4抑制剂（TAK-242），并在大鼠脊髓神经结扎（SNL）模型中使用von Frey试验评估机械性异常性疼痛。对TAK-242和Mincle抗体联合使用的效果进行等效线图分析。微阵列分析检测了抗体靶向的Mincle的特定区域。
所有Mincle抗体和TAK-242均以剂量依赖性方式显著减轻机械性异常性疼痛。然而，抗体产生的最大可能效应（MPE）范围广泛，从37.1%到91.8%，与TAK-242（88.7%）相当。TAK-242与MPE最高的抗体联合使用产生了相加的抗异常性疼痛作用。表位作图显示每种抗体靶向细胞外结构域，表位长度为5至15个氨基酸。
本研究证明了Mincle抗体在脊髓神经结扎模型中的抗异常性疼痛作用以及与TLR4抑制的相加相互作用，表明用其抗体阻断Mincle信号作为神经性疼痛新治疗策略的潜力。
