Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, 7624, Hungary.
János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.
J Neuroinflammation. 2018 Dec 3;15(1):335. doi: 10.1186/s12974-018-1364-5.
The regulatory role of capsaicin-sensitive peptidergic sensory nerves has been shown in acute inflammation, but little is known about their involvement in T/B-cell driven autoimmune arthritis. This study integratively characterized the function of these nerve endings in the proteoglycan-induced chronic arthritis (PGIA), a translational model of rheumatoid arthritis.
Peptidergic afferents were defunctionalized by resiniferatoxin (RTX) pretreatment in BALB/c mice, PGIA was induced by repeated antigen challenges. Hind paw volume, arthritis severity, grasping ability and the mechanonociceptive threshold were monitored during the 17-week experiment. Myeloperoxidase activity, vascular leakage and bone turnover were evaluated by in vivo optical imaging. Bone morphology was assessed using micro-CT, the intertarsal small joints were processed for histopathological analysis.
Following desensitization of the capsaicin-sensitive afferents, ankle edema, arthritis severity and mechanical hyperalgesia were markedly diminished. Myeloperoxidase activity was lower in the early, but increased in the late phase, whilst plasma leakage and bone turnover were not altered. Desensitized mice displayed similar bone spurs and erosions, but increased trabecular thickness of the tibia and bony ankylosis of the spine. Intertarsal cartilage thickness was not altered in the model, but desensitization increased this parameter in both the non-arthritic and arthritic groups.
This is the first integrative in vivo functional and morphological characterization of the PGIA mouse model, wherein peptidergic afferents have an important regulatory function. Their overall effect is proinflammatory by increasing acute inflammation, immune cell activity and pain. Meanwhile, their activation decreases spinal ankylosis, arthritis-induced altered trabecularity, and cartilage thickness in small joints.
辣椒素敏感肽能感觉神经在急性炎症中的调节作用已得到证实，但它们在 T/B 细胞驱动的自身免疫性关节炎中的作用知之甚少。本研究综合分析了这些神经末梢在蛋白聚糖诱导的慢性关节炎（PGIA）中的功能，PGIA 是类风湿关节炎的一种转化模型。
用树脂毒素（RTX）预处理使 BALB/c 小鼠的肽能传入神经失活，通过反复抗原刺激诱导 PGIA。在 17 周的实验过程中，监测后爪体积、关节炎严重程度、抓握能力和机械性痛觉阈值。通过体内光学成像评估髓过氧化物酶活性、血管渗漏和骨转换。使用 micro-CT 评估骨形态，对跗间小关节进行组织病理学分析。
辣椒素敏感传入神经脱敏后，踝关节肿胀、关节炎严重程度和机械性痛觉过敏明显减轻。早期髓过氧化物酶活性降低，但晚期增加，而血浆渗漏和骨转换没有改变。脱敏小鼠表现出相似的骨刺和侵蚀，但胫骨小梁厚度增加，脊柱骨性强直。模型中小关节软骨厚度没有改变，但脱敏增加了非关节炎和关节炎组的这一参数。
这是首次对 PGIA 小鼠模型进行体内功能和形态学综合分析，其中肽能传入神经具有重要的调节功能。它们的整体作用是通过增加急性炎症、免疫细胞活性和疼痛而具有促炎作用。同时，它们的激活减少了脊柱强直、关节炎引起的小梁改变和小关节软骨厚度的改变。
