ICBAS - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal;
J Immunol. 2013 Nov 1;191(9):4759-68. doi: 10.4049/jimmunol.1301752. Epub 2013 Sep 27.
Sepsis is the third most common cause of neonatal death, with Group B Streptococcus (GBS) being the leading bacterial agent. The pathogenesis of neonatal septicemia is still unsolved. We described previously that host susceptibility to GBS infection is due to early IL-10 production. In this study, we investigated whether triggering TLR2 to produce IL-10 is a risk factor for neonatal bacterial sepsis. We observed that, in contrast to wild-type (WT) pups, neonatal TLR2-deficient mice were resistant to GBS-induced sepsis. Moreover, if IL-10 signaling were blocked in WT mice, they also were resistant to sepsis. This increased survival rate was due to an efficient recruitment of neutrophils to infected tissues that leads to bacterial clearance, thus preventing the development of sepsis. To confirm that IL-10 produced through TLR2 activation prevents neutrophil recruitment, WT pups were treated with the TLR2 agonist Pam3CSK4 prior to nebulization with the neutrophil chemotactic agent LTB4. Neutrophil recruitment into the neonatal lungs was inhibited in pups treated with Pam3CSK4. However, the migration was restored in Pam3CSK4-treated pups when IL-10 signaling was blocked (either by anti-IL-10R mAb treatment or by using IL-10-deficient mice). Our findings highlight that TLR2-induced IL-10 production is a key event in neonatal susceptibility to bacterial sepsis.
败血症是导致新生儿死亡的第三大常见原因，而 B 型链球菌（GBS）是主要的细菌病原体。新生儿败血症的发病机制仍未得到解决。我们之前曾描述过，宿主对 GBS 感染的易感性是由于早期产生 IL-10。在这项研究中，我们研究了触发 TLR2 产生 IL-10 是否是新生儿细菌性败血症的一个危险因素。我们观察到，与野生型（WT）幼鼠相比，新生 TLR2 缺陷型小鼠对 GBS 诱导的败血症具有抗性。此外，如果在 WT 小鼠中阻断 IL-10 信号，它们也对败血症具有抗性。这种存活率的提高是由于有效的招募中性粒细胞到感染组织，从而导致细菌清除，从而防止败血症的发展。为了证实通过 TLR2 激活产生的 IL-10 可防止中性粒细胞募集，在使用中性粒细胞趋化剂 LTB4 雾化之前，用 TLR2 激动剂 Pam3CSK4 处理 WT 幼鼠。在 Pam3CSK4 处理的幼鼠中，中性粒细胞募集到新生肺中被抑制。然而，当阻断 IL-10 信号（通过抗 IL-10R mAb 处理或使用 IL-10 缺陷型小鼠）时，Pam3CSK4 处理的幼鼠中的迁移得到恢复。我们的研究结果表明，TLR2 诱导的 IL-10 产生是新生儿对细菌性败血症易感性的关键事件。
