Immunomodulatory role of proteinase-activated receptor-2.
Immunomodulatory role of proteinase-activated receptor-2.
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DOI：
10.1136/annrheumdis-2011-200869
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发表时间：
2012-09
影响因子：
27.4
通讯作者：
Ferrell WR
中科院分区：
文献类型：
--
作者：
Crilly A;Palmer H;Nickdel MB;Dunning L;Lockhart JC;Plevin R;McInnes IB;Ferrell WR
蛋白酶激活受体 2 (PAR2) 与炎症性关节病理有关。作者利用胶原诱导的关节炎模型 (CIA) 探索了 PAR2 调节适应性免疫途径的能力，从而促进自身免疫介导的关节损伤。使用 PAR2 基因缺失和其他方法来抑制或阻止 PAR2 激活，通过临床和组织学评分以及离体免疫分析来评估 CIA 的发生和进展。通过关节炎评分和关节损伤的组织学评估来评估，在 PAR2 缺陷小鼠或给予 PAR2 拮抗剂 (ENMD-1068) 或 PAR2 中和抗体 (SAM11) 的野生型小鼠中，CIA 的进展显着消除 (p<0.0001)。与野生型同窝小鼠相比，在离体回忆胶原蛋白刺激测定中，发现 PAR2 缺陷小鼠的淋巴结来源的细胞悬液产生的白细胞介素 (IL)-17 和 IFNγ 显着减少。此外，还观察到 TNFα、IL-6、IL-1β 和 IL-12 以及 GM-CSF 和 MIP-1α 的显着抑制。然而，各组之间的脾脏和淋巴结组织学没有差异，引流淋巴结细胞亚群也没有检测到任何差异。 PAR2 缺陷小鼠的抗胶原抗体滴度显着降低。这些数据支持 PAR2 在 CIA 发病机制中的重要作用，并表明该受体在炎症性关节炎的适应性模型中具有免疫调节作用。 PAR2 拮抗作用可能为治疗炎症性关节炎（在富含蛋白酶的环境中占主导地位）提供未来潜力。
Proteinase-activated receptor-2 (PAR2) has been implicated in inflammatory articular pathology. Using the collagen-induced arthritis model (CIA) the authors have explored the capacity of PAR2 to regulate adaptive immune pathways that could promote autoimmune mediated articular damage. Using PAR2 gene deletion and other approaches to inhibit or prevent PAR2 activation, the development and progression of CIA were assessed via clinical and histological scores together with ex vivo immune analyses. The progression of CIA, assessed by arthritic score and histological assessment of joint damage, was significantly (p<0.0001) abrogated in PAR2 deficient mice or in wild-type mice administered either a PAR2 antagonist (ENMD-1068) or a PAR2 neutralising antibody (SAM11). Lymph node derived cell suspensions from PAR2 deficient mice were found to produce significantly less interleukin (IL)-17 and IFNγ in ex vivo recall collagen stimulation assays compared with wild-type littermates. In addition, substantial inhibition of TNFα, IL-6, IL-1β and IL-12 along with GM-CSF and MIP-1α was observed. However, spleen and lymph node histology did not differ between groups nor was any difference detected in draining lymph node cell subsets. Anticollagen antibody titres were significantly lower in PAR2 deficient mice. These data support an important role for PAR2 in the pathogenesis of CIA and suggest an immunomodulatory role for this receptor in an adaptive model of inflammatory arthritis. PAR2 antagonism may offer future potential for the management of inflammatory arthritides in which a proteinase rich environment prevails.