Chronic TLR Stimulation Controls NLRP3 Inflammasome Activation through IL-10 Mediated Regulation of NLRP3 Expression and Caspase-8 Activation.
Chronic TLR Stimulation Controls NLRP3 Inflammasome Activation through IL-10 Mediated Regulation of NLRP3 Expression and Caspase-8 Activation.
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DOI：
10.1038/srep14488
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发表时间：
2015-09-28
影响因子：
4.6
通讯作者：
Kanneganti TD
中科院分区：
文献类型：
--
作者：
Gurung P;Li B;Subbarao Malireddi RK;Lamkanfi M;Geiger TL;Kanneganti TD
虽然促进Nod样受体（NLR）家族成员NLRP 3炎性体活化的分子机制开始被定义，但关于调节NLRP 3炎性体的机制知之甚少。急性（长达4小时）LPS刺激，随后是ATP经常用于激活巨噬细胞中的NLRP 3炎性体。有趣的是，我们观察到LPS许可NLRP 3的能力是短暂的，因为长时间（12至24小时）的LPS暴露是相对无效的引发刺激。这表明相对于急性LPS，慢性LPS暴露触发调节机制以抑制NLRP 3活化。从用LPS刺激24小时的巨噬细胞转移培养物上清液显著降低了幼稚巨噬细胞中ATP和尼日利亚菌素诱导的NLRP 3炎性小体活化。我们进一步鉴定了IL-10作为分泌的炎性小体耐受因子，其以自分泌方式起作用以控制NLRP 3炎性小体的活化。最后，我们证明了IL-10抑制NLRP 3表达以控制NLRP 3炎性体活化和随后的半胱天冬酶-8活化。总之，我们已经揭示了一种机制，通过这种机制，慢性而非急性LPS暴露诱导IL-10抑制NLRP 3炎性小体活化，以避免明显的炎症。
While the molecular mechanisms promoting activation of the Nod-like Receptor (NLR) family member NLRP3 inflammasome are beginning to be defined, little is known about the mechanisms that regulate the NLRP3 inflammasome. Acute (up to 4 hours) LPS stimulation, followed by ATP is frequently used to activate the NLRP3 inflammasome in macrophages. Interestingly, we observed that the ability of LPS to license NLRP3 is transient, as prolonged (12 to 24 hours) LPS exposure was a relatively ineffective priming stimulus. This suggests that relative to acute LPS, chronic LPS exposure triggers regulatory mechanisms to dampen NLRP3 activation. Transfer of culture supernatants from macrophages stimulated with LPS for 24 hours dramatically reduced ATP- and nigericin-induced NLRP3 inflammasome activation in naïve macrophages. We further identified IL-10 as the secreted inflammasome-tolerizing factor that acts in an autocrine manner to control activation of the NLRP3 inflammasome. Finally, we demonstrated that IL-10 dampens NLRP3 expression to control NLRP3 inflammasome activation and subsequent caspase-8 activation. In conclusion, we have uncovered a mechanism by which chronic, but not acute, LPS exposure induces IL-10 to dampen NLRP3 inflammasome activation to avoid overt inflammation.