Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2012;7(6):e39576. doi: 10.1371/journal.pone.0039576. Epub 2012 Jun 29.
Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS.
炎症小体是一种多蛋白复合物，可控制促炎细胞因子（如 IL-1β）的产生。炎症小体在控制肿瘤和感染的免疫以及自身免疫性疾病中起着重要作用，但控制人类炎症小体激活的机制在很大程度上尚不清楚。我们发现，人类活化的 CD4+CD45RO+记忆 T 细胞特异性抑制 P2X7R 介导的 NLRP3 炎症小体激活，而不影响 P2X7R 非依赖性 NLRP3 或 NLRP1 炎症小体激活。活化的记忆 T 细胞同时增加的 pro-IL-1β 产生掩盖了这种效应。IFNβ 的引发除了抑制 NLRP3 炎症小体外，还降低了 pro-IL-1β 的产生，从而揭示了对 NLRP3 炎症小体激活的抑制作用。IFNβ 通过涉及降低 P2X7R 信号的间接机制抑制 NLRP3 炎症小体激活。IFNβ 引发的人类 CD4+CD45RO+记忆 T 细胞对 pro-IL-1β 产生的抑制和 NLRP3 炎症小体激活的抑制部分是由可溶性 FasL 介导的，并且与下调的 P2X7R mRNA 表达和减少对单核细胞中 ATP 的反应有关。多发性硬化症（MS）患者的 CD4+CD45RO+记忆 T 细胞抑制 NLRP3 炎症小体激活的能力降低，但在体内用 IFNβ 治疗后，其抑制能力得到恢复。因此，我们的数据表明，人类 P2X7R 介导的 NLRP3 炎症小体激活受活化的 CD4+CD45RO+记忆 T 细胞调节，并提供了有关 IFNβ 在 MS 中发挥治疗作用的机制的新信息。
