Chicken cathelicidin-2 promotes IL-1(i secretion via the NLRP3 inflammasome pathway and serine proteases activity in LPS-primed murine neutrophils
Chicken cathelicidin-2 promotes IL-1(i secretion via the NLRP3 inflammasome pathway and serine proteases activity in LPS-primed murine neutrophils
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鸡 cathelicidin-2 通过 NLRP3 炎性体途径和 LPS 引发的鼠中性粒细胞中的丝氨酸蛋白酶活性促进 IL-1β 分泌
DOI：
10.1016/j.dci.2022.104377
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发表时间：
2022-02-26
影响因子：
2.9
通讯作者：
Fang, Rendong
中科院分区：
文献类型：
--
作者：
Peng, Lianci;Lu, Yi;Fang, Rendong
Cathelicidins 具有抗菌和免疫调节活性。先前的研究表明，鸡cathelicidin-2（CATH-2）通过LPS中和发挥强大的抗炎活性。然而，目前尚不清楚其他细胞内信号通路是否参与CATH-2免疫调节。因此，在 LPS 引发的中性粒细胞中研究了 CATH-2 介导的免疫反应。首先，测定 LPS 引发的中性粒细胞中炎症细胞因子的释放。结果显示，CATH-2显着促进IL-1(i和IL-1α的分泌，而IL-6和TNF-α不受影响。IL-1(i是炎症小体激活的关键指标。接下来，利用Nlrp3-/-、Asc-/-和Casp1-/-小鼠的中性粒细胞探索NLRP3炎症小体信号通路，结果显示CATH-2增强的IL-1(i释放完全此外，CATH-2 显着诱导 caspase-1 和 Gasdermin D (GSDMD) 的激活，但不影响 LPS 诱导的 IL-1(i 和 NLRP3) mRNA 表达，证明 CATH-2 是激活 NLRP3 炎症小体的第二个信号。此外，CATH-2 介导的 IL-1(i 分泌和 caspase-1 激活依赖于钾流出，但与钾流出无关。此外，使用不同的抑制剂研究了包括JNK、ERK和SyK在内的其他信号通路，结果表明这些信号通路抑制剂部分减弱了CATH-2增强的IL-1(i分泌，尤其是JNK抑制剂。最后，在中性粒细胞中研究了丝氨酸蛋白酶在CATH-2介导的NLRP3炎症小体激活中的作用，结果表明丝氨酸蛋白酶活性参与CATH-2增强了IL-1(i的分泌和caspase-1的激活。总之，在中性粒细胞中LPS引发后，CATH-2可以成为NLRP3炎症小体的激动剂。我们的研究增加了对鸡导管素的免疫调节作用的认识，并为鸡导管素介导的免疫反应提供了新的见解。
Cathelicidins have antimicrobial and immunomodulatory activities. Previous studies have shown that chicken cathelicidin-2 (CATH-2) exerts strong anti-inflammatory activity through LPS neutralization. However, it is still unclear whether other intracellular signaling pathways are involved in CATH-2 immunomodulation. Therefore, the CATH-2-meadiated immune response was investigated in LPS-primed neutrophils. Firstly, inflammatory cytokines release was determined in LPS-primed neutrophils. The results showed that CATH-2 significantly promoted secretion of IL-1(i and IL-1 alpha while IL-6 and TNF-alpha were not affected. IL-1(i is the key indicator of inflammasome activation. Next, NLRP3 inflammasome signaling pathway was explored using neutrophils of Nlrp3- /-, Asc-/- and Casp1-/- mice and the results showed that the CATH-2-enhanced IL-1(i release was completely abrogated, indicating it is NLRP3-dependent. Moreover, CATH-2 significantly induced activation of caspase-1 and gasdermin D (GSDMD) but did not affect LPS-induced mRNA expression of IL-1(i and NLRP3, demonstrating that CATH-2 serves as the second signal activating the NLRP3 inflammasome. Furthermore, CATH-2-mediated IL-1(i secretion and caspase-1 activation is dependent on potassium efflux but independent of P2X7R. In addition, other signaling pathways including JNK, ERK and SyK were investigated using different inhibitors and the results showed that these signaling pathway inhibitors partially attenuated CATH-2-enhanced IL-1(i secretion, especially the JNK inhibitor. Finally, the role of serine protease in CATH-2-mediated NLRP3 inflammasome activation was investigated in neutrophils and the results showed that serine protease activity is involved in CATH-2-enhanced IL-1(i secretion and caspase-1 activation. In conclusion, after LPS priming in neutrophils, CATH-2 can be an agonist of the NLRP3 inflammasome. Our study increases the understanding on immunomodulatory effects of chicken cathelicidins and provides new insight on chicken cathelicidins-mediated immune response.