Yanik Brandon M, Dauch Jacqueline R, Cheng Hsinlin T
Department of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Pain Res. 2020 Dec 29;13:3499-3512. doi: 10.2147/JPR.S264136. eCollection 2020.
Neurogenic inflammation is a major component of chronic neuropathic pain. Previously, we established the db/db mouse as an animal model of painful diabetic neuropathy (PDN) of type 2 diabetes. In the current study, we investigate the roles of interleukin (IL)-10, an anti-inflammatory cytokine, in the development of neurogenic inflammation and pain behavior in db/db mouse.
We first studied IL-10 expression in lumbar dorsal root ganglion (LDRG) neurons of db/db mice using immunohistochemistry, immunoblots, and reverse transcription polymerase chain reaction during the period of pain behavior (from 8 to 16 wk of age). To determine if the reduced IL-10 expression mediates the mechanical allodynia in db/db mice, we administered recombinant mouse IL-10 or saline (control) intraperitoneally to control db/+ and db/db mice starting at 8 wk of age. IL-10 treatment was repeated every other day for 2 wk until the mice reached 10 wk of age.
During the period of pain behavior, reduction of IL-10 protein and gene expression was detected in LDRG of db/db mice. Treatment with recombinant IL-10, from 8 to 10 wk of age, alleviates pain behaviors in db/db mice without affecting other diabetic parameters. In parallel, IL-10 treatment reduced the upregulation of nerve growth factor (NGF), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and high-affinity NGF receptor (Trk A) in LDRG, as well as the numbers of iNOS-positive Langerhans cells and CD-68-positive dermal dendritic cells in the hind-foot-pad skin in db/db mice.
Our findings suggest that the reduction in neuronal IL-10 increases inflammatory phenomena, ultimately contributing to PDN. These results suggest that the dysregulation of cytokine-mediated inflammation contributes to the development of PDN in db/db mice. Targeting this pathophysiologic mechanism could be an effective approach for treating PDN in type 2 diabetes.
神经源性炎症是慢性神经性疼痛的主要组成部分。此前，我们将db/db小鼠确立为2型糖尿病疼痛性糖尿病神经病变（PDN）的动物模型。在本研究中，我们探究抗炎细胞因子白细胞介素（IL）-10在db/db小鼠神经源性炎症和疼痛行为发展中的作用。
我们首先在疼痛行为期（8至16周龄），使用免疫组织化学、免疫印迹和逆转录聚合酶链反应研究db/db小鼠腰段背根神经节（LDRG）神经元中IL-10的表达。为确定IL-10表达降低是否介导db/db小鼠的机械性异常性疼痛，我们从8周龄开始给对照db/+和db/db小鼠腹腔注射重组小鼠IL-10或生理盐水（对照）。每隔一天重复进行IL-10治疗，持续2周，直至小鼠达到10周龄。
在疼痛行为期，db/db小鼠的LDRG中检测到IL-10蛋白和基因表达降低。8至10周龄期间用重组IL-10治疗可减轻db/db小鼠的疼痛行为，且不影响其他糖尿病参数。同时，IL-10治疗降低了db/db小鼠LDRG中神经生长因子（NGF）、诱导型一氧化氮合酶（iNOS）、肿瘤坏死因子（TNF）-α和高亲和力NGF受体（Trk A）的上调，以及后足垫皮肤中iNOS阳性朗格汉斯细胞和CD-68阳性真皮树突状细胞的数量。
我们的研究结果表明，神经元IL-10的减少会增加炎症现象，最终导致PDN。这些结果表明，细胞因子介导的炎症失调促成了db/db小鼠PDN的发展。针对这一病理生理机制可能是治疗2型糖尿病PDN的有效方法。
