Hu Rong, Zhang Jintao, Liu Xuemei, Huang Dong, Cao Yu-Qing
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA.
J Pain Res. 2021 Apr 6;14:893-906. doi: 10.2147/JPR.S301343. eCollection 2021.
Nerve injury-induced mechanical hyper-sensitivity, in particular stroking-induced dynamic allodynia, is highly debilitating and difficult to treat. Previous studies indicate that the immunosuppressive regulatory T (Treg) cells modulate the magnitude of punctate mechanical allodynia resulting from sciatic nerve injury. However, whether enhancing Treg-mediated suppression attenuates dynamic allodynia is not known. In the present study, we addressed this knowledge gap by treating mice with low-dose interleukin-2 (ld-IL2) injections or adoptive transfer of Treg cells.
Female Swiss Webster mice received daily injections of ld-IL2 (1 μg/mouse, intraperitoneally) either before or after unilateral spared nerve injury (SNI). Male C57BL/6J mice received adoptive transfer of 1 x 10 Treg cells 3 weeks post-SNI. The responses to punctate and dynamic mechanical stimuli on the hindpaw were monitored before and up to 4-6 weeks post-SNI. We also compared the distribution of Treg cells and CD3 total T cells after SNI and/or ld-IL2 treatment.
Ld-IL2 pretreatment in female Swiss Webster mice completely blocked the development of SNI-induced dynamic mechanical allodynia and reduced the magnitude of punctate allodynia. Delayed ld-IL2 treatment in female mice significantly attenuated the morphine-resistant punctate and dynamic allodynia at 3-5 weeks post-SNI. Adoptive transfer of Treg cells to male C57BL/6J mice 3 weeks post-SNI effectively reversed the persistent punctate and dynamic allodynia, supporting that the effect of ld-IL2 is mediated through endogenous Treg cells, and is likely independent of mouse strain and sex. Neither ld-IL2 treatment nor Treg transfer affected the basal responses to punctate or brush stimuli. Ld-IL2 significantly increased the frequency of Treg cells among total CD3 T cells in the injured sciatic nerves but not in the uninjured nerves or the dorsal root ganglia, suggesting the injured nerve as ld-IL2's site of action.
Collectively, results from the present study supports Treg as a cellular target and ld-IL2 as a potential therapeutic option for nerve injury-induced persistent punctate and dynamic mechanical allodynia.
神经损伤诱发的机械性超敏反应，尤其是轻触诱发的动态性痛觉过敏，会严重削弱机体功能且难以治疗。既往研究表明，免疫抑制性调节性T（Treg）细胞可调节坐骨神经损伤所致点状机械性痛觉过敏的程度。然而，增强Treg介导的抑制作用是否能减轻动态性痛觉过敏尚不清楚。在本研究中，我们通过给小鼠注射低剂量白细胞介素-2（ld-IL2）或过继转移Treg细胞来填补这一知识空白。
雌性瑞士韦伯斯特小鼠在单侧保留神经损伤（SNI）之前或之后，每天接受ld-IL2注射（1μg/小鼠，腹腔注射）。雄性C57BL/6J小鼠在SNI后3周接受1×10个Treg细胞的过继转移。在SNI前及SNI后长达4 - 6周监测后爪对点状和动态机械刺激的反应。我们还比较了SNI和/或ld-IL2治疗后Treg细胞和CD3总T细胞的分布情况。
雌性瑞士韦伯斯特小鼠的ld-IL2预处理完全阻断了SNI诱发的动态机械性痛觉过敏的发展，并减轻了点状痛觉过敏的程度。雌性小鼠延迟给予ld-IL2治疗可在SNI后3 - 5周显著减轻吗啡抵抗性点状和动态痛觉过敏。在SNI后3周将Treg细胞过继转移至雄性C57BL/6J小鼠可有效逆转持续性点状和动态痛觉过敏，这支持了ld-IL2的作用是通过内源性Treg细胞介导的，且可能与小鼠品系和性别无关。ld-IL2治疗和Treg转移均未影响对点状或轻刷刺激的基础反应。ld-IL2显著增加了损伤坐骨神经中总CD3 T细胞中Treg细胞的频率，但在未损伤神经或背根神经节中未增加，这表明损伤神经是ld-IL2的作用部位。
总体而言，本研究结果支持Treg作为细胞靶点以及ld-IL2作为神经损伤诱发的持续性点状和动态机械性痛觉过敏的潜在治疗选择。
