Infertility Clinic, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Center for Clinical Research, Samsung Biomedical Research Institute, Seoul, Korea.
Mol Hum Reprod. 2022 Apr 1;28(4). doi: 10.1093/molehr/gaac007.
The NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic multi-protein complex that induces inflammation and is known to be regulated negatively by autophagy. Previous studies reported an abnormal induction of autophagy linked to progesterone resistance in human endometriotic cells. Therefore, an aberrant autophagy induction response to progesterone might contribute to the altered inflammatory response observed in endometriotic tissues. To evaluate this hypothesis, we elucidate whether regulation of the NLRP3 inflammasome by ovarian steroids is mediated by autophagy in human endometrial stromal cells (normal endometrial stromal cells (NESCs)) from patients with uterine leiomyoma (presumed normal) and whether abnormal autophagy induction in endometriotic cyst stromal cells (ECSCs) affects NLRP3 inflammasome-induced interleukin-1β (IL-1β) production. Our results show that estrogen enhanced NLRP3 inflammasome activation in NESCs, resulting in increased IL-1β production. Progesterone decreased NLRP3 inflammasome activity with an increase in autophagy induction in estrogen-treated NESCs. Inhibition of NLRP3 inflammasome activity by progesterone was blocked by autophagy inhibition. However, progesterone failed to change NLRP3 inflammasome activity and autophagy induction in estrogen-treated ECSCs. In contrast, dienogest, a specific progesterone receptor agonist, reduced NLRP3 inflammasome-mediated IL-1β production through autophagy induction in ECSCs. Furthermore, autophagy induction was decreased and NLRP3 inflammasome activity was increased in endometriotic tissues, which was reversed by preoperative administration of dienogest. In conclusion, our results suggest that progesterone inhibits NLRP3 inflammasome activation through autophagy in endometrial stromal cells. However, this inhibitory effect is attenuated in endometriotic stromal cells due to an aberrant autophagic response to progesterone, which could lead to an altered inflammatory response in endometriosis.
NOD 样受体含 pyrin 结构域蛋白 3（NLRP3）炎性小体是一种细胞溶质多蛋白复合物，可诱导炎症，并已知受自噬负调控。先前的研究报道，在人类子宫内膜异位症细胞中，孕激素抵抗与自噬的异常诱导有关。因此，孕激素诱导的自噬异常反应可能导致子宫内膜异位症组织中观察到的炎症反应改变。为了评估这一假设，我们阐明了卵巢类固醇对 NLRP3 炎性小体的调节是否通过人子宫内膜基质细胞（来自子宫肌瘤患者的正常子宫内膜基质细胞（NESCs））中的自噬介导，以及子宫内膜异位症囊肿基质细胞（ECSCs）中异常的自噬诱导是否影响 NLRP3 炎性小体诱导的白细胞介素-1β（IL-1β）产生。我们的结果表明，雌激素增强了 NESCs 中 NLRP3 炎性小体的激活，导致 IL-1β 产生增加。孕激素降低了雌激素处理的 NESCs 中 NLRP3 炎性小体的活性，并增加了自噬诱导。孕激素抑制 NLRP3 炎性小体活性被自噬抑制阻断。然而，孕激素未能改变雌激素处理的 ECSCs 中 NLRP3 炎性小体的活性和自噬诱导。相反，地诺孕素，一种特异性孕激素受体激动剂，通过 ECSCs 中的自噬诱导降低了 NLRP3 炎性小体介导的 IL-1β 产生。此外，子宫内膜异位症组织中的自噬诱导减少，NLRP3 炎性小体活性增加，术前给予地诺孕素可逆转这种情况。总之，我们的结果表明，孕激素通过子宫内膜基质细胞中的自噬抑制 NLRP3 炎性小体的激活。然而，由于孕激素诱导的自噬反应异常，这种抑制作用在子宫内膜异位症基质细胞中减弱，这可能导致子宫内膜异位症中的炎症反应改变。
