Characterization of the Protective Role of Regulatory T Cells in Experimental Periapical Lesion Development and Their Chemoattraction Manipulation as a Therapeutic Tool.
Characterization of the Protective Role of Regulatory T Cells in Experimental Periapical Lesion Development and Their Chemoattraction Manipulation as a Therapeutic Tool.
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DOI：
10.1016/j.joen.2015.09.022
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发表时间：
2016-01
影响因子：
4.2
通讯作者：
Garlet GP
中科院分区：
文献类型：
--
作者：
Francisconi CF;Vieira AE;Biguetti CC;Glowacki AJ;Trombone AP;Letra A;Menezes Silva R;Sfeir CS;Little SR;Garlet GP
根尖周病变的发病机制是由宿主促炎免疫反应与抵抗抗炎和修复反应之间的平衡决定的，其中包括作为潜在免疫调节剂的调节性 T 细胞 (Treg)。在本研究中，我们（以因果关系的方式）研究了 CCL22-CCR4 轴在 Tregs 迁移到根尖周区域中的参与以及 Tregs 在确定根尖周病变结果中的作用。在 C57Bl/6 (WT) 和 CCR4KO 小鼠中诱导根尖损伤（牙髓暴露和细菌接种），并用抗 GITR 治疗以抑制 Tregs 功能，或者用释放 CCL22 的 PLGA 颗粒治疗，以诱导 Tregs 的位点特异性迁移。治疗后，分析病变的 Tregs 流入和表型、总体根尖骨丢失以及炎症/免疫和伤口愈合标记物表达（通过 RealTimePCRarray 分析）。抗 GITR 或 CCR4 耗竭导致的 Tregs 抑制导致根尖周病变严重程度显着增加，与促炎性、Th1、Th17 和组织破坏标记物的上调相关，同时 Tregs 和愈合标记物表达减少。根管系统中 CCL22 的局部释放导致以 CCR4 依赖性方式促进 Tregs 迁移，从而阻止根尖周病变进展，这与促炎性、Th1、Th17 和组织破坏标记物的下调以及 Tregs 和愈合标记物表达的增加相关。由于天然和 CCL22 诱导的 Tregs 迁移将活动性病变转变为不活动表型，因此 Tregs 趋化剂可能是根尖周病变临床管理的一种有希望的策略。
The pathogenesis of periapical lesions is determined by the balance between host pro-inflammatory immune response and counteracting anti-inflammatory and reparative responses, which include regulatory T cells (Tregs) as potential immunoregulatory agents. In this study, we investigated (in a cause-and-effect manner) the involvement of CCL22-CCR4 axis in Tregs migration to the periapical area and the role of Tregs in the determination of outcomes in periapical lesions. Periapical lesions were induced in C57Bl/6 (WT) and CCR4KO mice (pulp exposure and bacterial inoculation), and treated with anti-GITR to inhibit Tregs function or alternatively with CCL22-releasing, PLGA particles to induce site-specific migration of Tregs. Post treatment, lesions were analyzed for Tregs influx and phenotype, overall periapical bone loss and inflammatory/immunological and wound healing markers expression (analyzed by RealTimePCRarray). Tregs inhibition by anti-GITR or CCR4 depletion results in a significant increase in periapical lesions severity, associated with upregulation of proinflammatory, Th1, Th17 and tissue destruction markers in parallel with decreased Tregs and healing markers expression. The local release of CCL22 in the root canal system resulted in the promotion of Tregs migration in a CCR4-dependent manner, leading to the arrest of periapical lesions progression, associated with downregulation of pro-inflammatory, Th1, Th17 and tissue destruction markers in parallel with increased Tregs and healing markers expression. Since the natural and CCL22 induced Tregs migration switch active lesion into inactivity phenotype, Tregs chemoattractant may be a promisor strategy for the clinical management of periapical lesions.