Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis.
Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis.
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DOI：
10.1002/art.37862
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发表时间：
2013-05
影响因子：
--
通讯作者：
Firestein, Gary S.
中科院分区：
文献类型：
--
作者：
Sluka, Kathleen A.;Rasmussen, Lynn A.;Edgar, Meghan M.;O'Donnell, James M.;Walder, Roxanne Y.;Kolker, Sandra J.;Boyle, David L.;Firestein, Gary S.
酸感应离子通道3 （ASIC3）位于痛觉感受器上，在pH降低时被激活，在肌肉骨骼疼痛中起重要作用。我们最近发现pH降低激活了位于成纤维细胞样滑膜细胞（FLS）上的ASIC3。由于FLS是炎症过程中的关键细胞，我们测试了患有关节炎的asic3缺陷小鼠相对于对照组是否改变了炎症和疼痛。通过注射抗II型胶原抗体鸡尾酒诱导胶原抗体关节炎（CAIA）诱导关节炎。评估ASIC3−/−和ASIC3+/+小鼠的炎症和疼痛参数。通过临床关节炎评分、关节直径、关节组织学分析和滑膜基因表达的qPCR来衡量疾病严重程度。通过检查关节和爪子的戒断阈值以及测量小鼠的身体活动水平来测量疼痛行为。在ph值降低的情况下，用FLS的活/死试验评估细胞死亡。令人惊讶的是，与ASIC3+/+小鼠相比，CAIA的ASIC3−/−小鼠表现出明显增加的关节炎症、关节破坏和关节组织中IL-6、MMP-3和MMP-13的表达。当暴露于pH 6.0时，ASIC3+/+ FLS在白细胞介素-1β的存在下显示细胞死亡增加，而白细胞介素-1β在ASIC3−/−FLS中被废除。尽管疾病严重程度增强，但ASIC3 - / -小鼠不会发生足部机械过敏，并表现出更高水平的身体活动。这些数据与ASIC3在炎性关节炎中发挥保护作用的假设一致，ASIC3通过增强滑膜细胞死亡来限制炎症，从而降低疾病严重程度并产生疼痛以减少关节使用。
Through its location on nociceptors, acid sensing ion channel 3 (ASIC3) is activated by decreases in pH and plays a significant role in musculoskeletal pain. We recently showed that decreases in pH activate ASIC3 located on fibroblast-like synoviocytes (FLS). Since FLS are key cells in the inflammatory process we tested if ASIC3-deficient mice with arthritis have altered inflammation and pain relative to controls. Arthritis was induced by injection of a cocktail of anti-type II collagen antibodies induced collagen antibodyarthritis (CAIA). Inflammation and pain parameters in ASIC3−/− and ASIC3+/+ mice were assessed. Disease severity was measured with clinical arthritis scores, joint diameters, histological analysis of joints, and qPCR for synovial gene expression. Pain behaviors were measured by examining withdrawal thresholds of the joint and paw and by measuring physical activity levels in mice. Cell death was assessed with a Live/Dead assay in FLS in response to decreases in pH. Surprisingly, ASIC3−/− mice with CAIA demonstrated significantly increased joint inflammation, joint destruction and expression of IL-6, MMP-3 and MMP-13 in joint tissue compared to ASIC3+/+ mice. ASIC3+/+ FLS show enhanced cell death when exposed to pH 6.0 in the presence of interleukin-1β that is abolished in ASIC3−/− FLS. Despite enhanced disease severity, ASIC3−/− mice do not develop mechanical hypersensitivity of the paw and show greater levels of physical activity. These data are consistent with the hypothesis that ASIC3 plays a protective role in inflammatory arthritis conditions by limiting inflammation through enhanced synoviocyte cell death to reduce disease severity and produce pain to reduce joint use.
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DOI：
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发表时间：
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期刊：
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影响因子：
--
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