Activation of the NLRP3 Inflammasome Pathway by Prokineticin 2 in Testicular Macrophages of Uropathogenic Escherichia coli- Induced Orchitis
Activation of the NLRP3 Inflammasome Pathway by Prokineticin 2 in Testicular Macrophages of Uropathogenic Escherichia coli- Induced Orchitis
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泌尿道致病性大肠杆菌引起的睾丸炎的睾丸巨噬细胞中前动力蛋白 2 激活 NLRP3 炎症小体途径
DOI：
10.3389/fimmu.2019.01872
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发表时间：
2019-08-14
影响因子：
7.3
通讯作者：
Zhao, Kai
中科院分区：
文献类型：
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作者：
Li, Ying;Su, Yufang;Zhao, Kai
众所周知，生殖道感染会导致睾丸炎症损伤，导致IL-1 β等促炎细胞因子增加，并导致精子质量下降。前动力蛋白2（PK 2）是一种分泌性蛋白，与炎症组织中促炎细胞因子的分泌密切相关。据报道，PK 2的增加与IL-1 β的上调有关，但其潜在机制仍不清楚。在此，我们阐明了在致尿路感染大肠杆菌（UPEC）感染的大鼠模型中，PK 2在睾丸巨噬细胞（TM）中上调，这诱导了NLRP 3炎性体途径的激活以促进IL-1 β分泌。给予PK 2抑制剂可减轻炎症损伤并抑制IL-1 β分泌。此外，PK 2促进NLRP 3的表达和在体外用UPEC攻击后从TM释放裂解的IL-1 β到上清液中。上清液中的IL-1 β通过抑制编码酶P450 SCC和P450 c17的基因的表达来影响Leydig细胞，这两种酶参与睾酮的产生。总的来说，我们揭示了在UPEC诱导的睾丸炎中TM中增加的PK 2水平可能通过激活NLRP 3途径损害睾酮合成。我们的研究为炎症相关性男性不育的机制提供了新的见解，并为男性不育的抗炎治疗提供了新的靶点。
Infections of the reproductive tract are known to contribute to testicular inflammatory impairment, leading to an increase of pro-inflammatory cytokines such as IL-1 beta, and a decline in sperm quality. Prokineticin 2 (PK2), a secretory protein, is closely associated with the secretion of pro-inflammatory cytokines in inflamed tissue. It was reported that increased PK2 is related to the upregulation of IL-1 beta, but the underlying mechanism remains elusive. Here, we illustrated that PK2 was upregulated in testicular macrophages (TM) in a rat model of uropathogenic Escherichia coli (UPEC) infection, which induced the activation of the NLRP3 inflammasome pathway to boost IL-1 beta secretion. Administration of PK2 inhibitor alleviated the inflammatory damage and suppressed IL-1 beta secretion. Moreover, PK2 promoted NLRP3 expression and the release of cleaved IL-1 beta from TM to the supernatants after the challenge with UPEC in vitro. IL-1 beta in the supernatants affected Leydig cells by suppressing the expression of genes encoding for the enzymes P450scc and P450c17, which are involved in testosterone production. Overall, we revealed that increased PK2 levels in TM in UPEC-induced orchitis may impair testosterone synthesis via the activation of the NLRP3 pathway. Our study provides a new insight into the mechanisms underlying inflammation-associated male infertility and suggests an anti-inflammatory therapeutic target for male infertility.