PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis
PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis
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DOI：
10.1073/pnas.0809422106
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发表时间：
2009-04-14
影响因子：
11.1
通讯作者：
Ayala, Alfred
中科院分区：
文献类型：
--
作者：
Huang, Xin;Venet, Fabienne;Ayala, Alfred
脓毒症是世界范围内死亡的主要原因，涉及过度炎症反应和细菌清除效率低下的伴随表达。巨噬细胞的功能是关键的发展，这两个方面在脓毒症，然而，这些变化的机制仍不清楚。在这里，我们报告说，PD-1：PD-L途径似乎是脓毒症的结果的决定因素，调节抗菌免疫反应的有效性和损害之间的微妙平衡。为此，我们观察到PD-1（-/-）小鼠明显免受败血症的致死性，伴随着减少的细菌负荷和抑制的炎性细胞因子反应。在某种程度上，这是PD-1作用的巨噬细胞特异性方面，我们发现以下内容：首先，腹腔巨噬细胞在脓毒症期间表达显著更高水平的PD-1，这与它们的细胞功能障碍的发展相关;第二，当腹腔巨噬细胞耗尽时，（使用氯膦酸盐脂质体），动物的杀菌能力降低，它们的炎性细胞因子水平升高，并且对脓毒性致死的保护减弱;第三，脓毒症小鼠和脓毒性休克患者的血液单核细胞PD-1水平均显著升高。总之，这些数据表明PD-1不仅可能是巨噬细胞/单核细胞的功能障碍性标志物/效应物，而且可能是设计调节先天免疫应答的措施的潜在治疗靶标，从而预防脓毒症的有害影响。
Sepsis, a leading cause of death worldwide, involves concomitant expression of an overzealous inflammatory response and inefficient bacterial clearance. Macrophage function is pivotal to the development of these two aspects during sepsis; however, the mechanisms underlying these changes remain unclear. Here we report that the PD-1:PD-L pathway appears to be a determining factor of the outcome of sepsis, regulating the delicate balance between effectiveness and damage by the antimicrobial immune response. To this end we observed that PD-1(-/-) mice were markedly protected from the lethality of sepsis, accompanied by a decreased bacterial burden and suppressed inflammatory cytokine response. To the extent that this is a macrophage-specific aspect of the effects of PD-1, we found the following: first, peritoneal macrophages expressed significantly higher levels of PD-1 during sepsis, which was associated with their development of cellular dysfunction; second, when peritoneal macrophages were depleted (using clodronate liposomes) from PD-1(-/-) mice, the animals' bactericidal capacity was lowered, their inflammatory cytokine levels were elevated, and protection from septic lethality was diminished; and third, blood monocytes from both septic mice and patients with septic shock shared markedly increased PD-1 levels. Together, these data suggest that PD-1 may not only be a dysfunctional marker/effector of macrophages/monocytes, but may also be a potential therapeutic target for designing measures to modulate the innate immune response, thereby preventing the detrimental effects of sepsis.