TRPA1 Ion Channel Determines Beneficial and Detrimental Effects of GYY4137 in Murine Serum-Transfer Arthritis
TRPA1 Ion Channel Determines Beneficial and Detrimental Effects of GYY4137 in Murine Serum-Transfer Arthritis
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DOI：
10.3389/fphar.2019.00964
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发表时间：
2019-09-04
影响因子：
5.6
通讯作者：
Pinter, Erika
中科院分区：
文献类型：
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作者：
Batai, Istvan Z.;Sar, Cecilia Papaine;Pinter, Erika
硫化物对类风湿关节炎的痛觉和炎症反应的调节以及硫化物激活瞬时受体电位锚蛋白1(TRPA1)离子通道的作用已被充分证实。本研究旨在探讨硫化物供体GYY4137对类风湿关节炎大鼠模型K/BxN血清转移性关节炎的影响。TRPA1和生长抑素sst4受体野生型(WT)和基因敲除小鼠接受K/BxN血清转移，每日给予GYY4137治疗。记录炎症的功能和生化征象，以及组织学特征。其中包括用动态足底感觉测量法检测后爪机械痛敏，用体积测量法检测后爪体积，以及倒挂至失败的时间。分别对后肢红斑、浮肿、胫颧骨关节被动活动范围进行评分。用放射免疫法检测多硫化物对TRPA1野生型和基因敲除小鼠感觉神经末梢生长抑素释放的影响。GYY4137通过冷氰解发现了多硫化物的形成。GYY4137可加重TRPA1基因敲除小鼠的机械性痛觉过敏，但可改善野生型小鼠的痛觉过敏。GYY4137降低了TRPA1野生型动物的关节炎评分。GYY4137治疗后，TRPA1基因敲除小鼠的髓过氧化物酶活性、血浆渗出和后爪皮下MIP-2水平均增加。Sst4受体的遗传缺失不会改变机械性痛觉过敏、水肿形成、悬吊能力、关节炎评分、血浆渗出或髓过氧化物酶活性。GYY4137给药后，TRPA1WT动物的软骨破坏较小。多硫化钠引起小鼠神经末梢TRPA1依赖的生长抑素释放。GYY4137释放出的硫化物很容易被次氯酸盐转化为多硫化物。多硫化物可有效激活中国仓鼠卵巢(CHO)细胞表达的人TRPA1受体。根据我们的资料，GYY4137的保护作用是通过TRPA1介导的，而在K/BxN血清转移性关节炎小鼠模型中，其有害作用不依赖于离子通道。在炎症组织的酸性pH下，硫化物从GYY4137中释放出来，并与中性粒细胞衍生的次氯酸盐发生反应。生成的多硫化物可能与TRPA1介导的抗伤害性和抗炎以及TRPA1非依赖的促炎作用有关。
Modulation of nociception and inflammation by sulfide in rheumatoid arthritis and activation of transient receptor potential ankyrin 1 (TRPA1) ion channels by sulfide compounds are well documented. The present study aims to investigate TRPA1-mediated effects of sulfide donor GYY4137 in K/BxN serum-transfer arthritis, a rodent model of rheumatoid arthritis. TRPA1 and somatostatin sst4 receptor wild-type (WT) and knockout mice underwent K/BxN serum transfer and were treated daily with GYY4137. Functional and biochemical signs of inflammation were recorded, together with histological characterization. These included detection of hind paw mechanical hyperalgesia by dynamic plantar esthesiometry, hind paw volume by plethysmometry, and upside-down hanging time to failure. Hind paw erythema, edema, and passive movement range of tibiotarsal joints were scored. Somatostatin release from sensory nerve endings of TRPA1 wild-type and knockout mice in response to polysulfide was detected by radioimmunoassay. Polysulfide formation from GYY4137 was uncovered by cold cyanolysis. GYY4137 aggravated mechanical hyperalgesia in TRPA1 knockout mice but ameliorated it in wild-type ones. Arthritis score was lowered by GYY4137 in TRPA1 wild-type animals. Increased myeloperoxidase activity, plasma extravasation, and subcutaneous MIP-2 levels of hind paws were detected in TRPA1 knockout mice upon GYY4137 treatment. Genetic lack of sst4 receptors did not alter mechanical hyperalgesia, edema formation, hanging performance, arthritis score, plasma extravasation, or myeloperoxidase activity. TRPA1 WT animals exhibited smaller cartilage destruction upon GYY4137 administration. Sodium polysulfide caused TRPA1-dependent somatostatin release from murine nerve endings. Sulfide released from GYY4137 is readily converted into polysulfide by hypochlorite. Polysulfide potently activates human TRPA1 receptors expressed in Chinese hamster ovary (CHO) cells. According to our data, the protective effect of GYY4137 is mediated by TRPA1, while detrimental actions are independent of the ion channel in the K/BxN serum-transfer arthritis model in mice. At acidic pH in inflamed tissue sulfide is released from GYY4137 and reacts with neutrophil-derived hypochlorite. Resulting polysulfide might be responsible for TRPA1 -mediated antinociceptive and anti-inflammatory as well as TRPA1 -independent pro-inflammatory effects.