PARP-1 inhibition prevents CNS migration of dendritic cells during EAE, suppressing the encephalitogenic response and relapse severity
PARP-1 inhibition prevents CNS migration of dendritic cells during EAE, suppressing the encephalitogenic response and relapse severity
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DOI：
10.1177/1352458511399113
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发表时间：
2011-07-01
影响因子：
5.8
通讯作者：
Chiarugi, Alberto
中科院分区：
文献类型：
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作者：
Cavone, Leonardo;Aldinucci, Alessandra;Chiarugi, Alberto
背景：聚adp核糖聚合酶-1 （PARP-1）的药理学抑制剂目前在各种恶性肿瘤的临床试验中进行了评估，但有趣的是，在包括实验性自身免疫性脑脊髓炎（EAE）在内的自身免疫性疾病的临床前模型中也证明了显着的疗效。目的：本研究的目的是确定这些药物抑制致脑反应的分子机制；同样，临床相关的PARP-1抑制剂治疗后范例是否可以预防EAE复发。方法：采用体外技术（骨髓源性培养DC）和体内慢性或复发缓解（RR） EAE模型。结果：我们报道了两种结构不相关的PARP-1抑制剂对培养的小鼠骨髓源性树突状细胞（DCs）的NF κ B激活、成熟、细胞因子产生和APC功能产生负性调节。PARP-1抑制剂还能降低卵清蛋白免疫小鼠引流淋巴结中迁移的dc的数量和APC功能。在患有慢性EAE的C57Bl小鼠或患有RR型EAE的SJL小鼠中，PARP-1的药理抑制可减少中枢神经系统DC迁移和脱髓鞘以及神经功能损害，其程度与强效免疫抑制剂环孢素a相似。值得注意的是，在疾病第一阶段后注射PARP-1抑制剂可降低复发率和严重程度，以及脊髓自身反应性Th17细胞的数量。在这种临床相关的治疗模式下，PARP抑制剂也抑制了致脑反应的表位扩散。结论：总体而言，数据强调PARP-1抑制剂与MS治疗和自身免疫抑制的潜在相关性。
Background: Pharmacological inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are currently evaluated in clinical trials for various malignancies but, interestingly, also proved of remarkable efficacy in preclinical models of autoimmune disorders including experimental autoimmune encephalomyelitis (EAE).Objectives: The objectives of the study were to determine molecular mechanisms underlying suppression of the encephalitogenic response by these drugs; likewise, whether clinically-relevant post-treatment paradigms with PARP-1 inhibitors could prevent EAE relapses.Methods: Adopted both in vitro techniques (bone marrow-derived cultured DC) as well as in vivo models of chronic or relapsing-remitting (RR) EAE.Results: We report that two structurally unrelated PARP-1 inhibitors negatively regulated NF kappa B activation, as well as maturation, cytokine production and APC function of cultured mouse bone marrow-derived dendritic cells (DCs). PARP-1 inhibitors also reduced the number and APC function of DCs migrating in the draining lymph nodes of ovalbumin-immunized mice. In C57Bl mice with chronic EAE or SJL mice with RR EAE, pharmacological inhibition of PARP-1 reduced CNS DC migration and demyelination as well as neurological impairment to an extent similar to that achieved with the potent immunosuppressant cyclosporine A. Remarkably, PARP-1 inhibitors injected after the first phase of disease reduced relapse incidence and severity, as well as the spinal cord number of autoreactive Th17 cells. Under this clinically-relevant treatment paradigm, PARP inhibitors also suppressed epitope spreading of the encephalitogenic response.Conclusions: Overall, data underscore the potential relevance of PARP-1 inhibitors to MS therapy and suppression of autoimmunity.