Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection
Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection
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DOI：
10.1038/nm.2156
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发表时间：
2010-06-01
期刊：
影响因子：
82.9
通讯作者：
Liew, Foo Y.
中科院分区：
文献类型：
--
作者：
Alves-Filho, Jose C.;Sonego, Fabiane;Liew, Foo Y.
脓毒症是细菌感染后的全身性炎症性疾病，死亡率高，治疗选择有限（1，2）。在这里，我们表明，白细胞介素-33（IL-33）降低盲肠结扎穿孔（CLP）实验性脓毒症小鼠的死亡率。IL-33处理的小鼠比未处理的小鼠产生增加的中性粒细胞流入腹膜腔和更有效的细菌清除。IL-33降低了全身而非局部的促炎反应，并且它不诱导T辅助细胞1型（T（H）1）向T（H）2转变。趋化因子受体CXCR 2对于将中性粒细胞从循环中募集到感染部位至关重要（3）。中性粒细胞中Toll样受体（TLR）的激活下调CXCR 2表达并损害中性粒细胞迁移（4）。我们在这里表明，IL-33防止下调CXCR 2和抑制趋化诱导的激活TLR 4在小鼠和人类中性粒细胞。此外，我们发现IL-33通过抑制G蛋白偶联受体激酶-2（GRK 2）（一种诱导趋化因子受体内化的丝氨酸-苏氨酸蛋白激酶）的表达，逆转了TLR 4诱导的中性粒细胞中CXCR 2表达的降低（5，6）。最后，我们发现没有从脓毒症中恢复的个体比那些恢复的个体具有显著更多的可溶性ST 2（sST 2，IL-33的诱饵受体）。总之，我们的研究结果表明了IL-33的一种以前未描述的作用机制，并表明IL-33在脓毒症中的治疗潜力。
Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options(1,2). Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection(3). Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration(4). We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors(5,6). Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.