Navarro-Pando José M, Alcocer-Gómez Elísabet, Castejón-Vega Beatriz, Navarro-Villarán Elena, Condés-Hervás Mónica, Mundi-Roldan María, Muntané Jordi, Pérez-Pulido Antonio J, Bullon Pedro, Wang Chun, Hoffman Hal M, Sanz Alberto, Mbalaviele Gabriel, Ryffel Bernhard, Cordero Mario D
Cátedra de Reproducción y Genética Humana del Instituto para el Estudio de la Biología de la Reproducción Humana (INEBIR)-Universidad Europea del Atlántico (UNEATLANTICO)-Fundación Universitaria Iberoamericana (FUNIBER), Seville, Spain.
Departamento de Psicología Experimental, Facultad de Psicología, Universidad de Sevilla, Seville, Spain.
Sci Adv. 2021 Jan 1;7(1). doi: 10.1126/sciadv.abc7409. Print 2021 Jan.
Inflammation is a hallmark of aging and is negatively affecting female fertility. In this study, we evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in WT mice during reproductive aging. High expression of NLRP3, caspase-1, and IL-1β was also observed in granulosa cells from patients with ovarian insufficiency. Ablation of NLRP3 improved the survival and pregnancy rates and increased anti-Müllerian hormone levels and autophagy rates in ovaries. Deficiency of NLRP3 also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.
炎症是衰老的一个标志，并且对女性生育能力有负面影响。在本研究中，我们评估了NLRP3炎性小体在卵巢衰老和女性生育能力中的作用。在生殖衰老过程中，野生型小鼠卵巢中观察到NLRP3随年龄增长而表达增加。在卵巢功能不全患者的颗粒细胞中也观察到NLRP3、半胱天冬酶-1和白细胞介素-1β的高表达。敲除NLRP3可提高卵巢的存活率和妊娠率，并增加抗苗勒管激素水平和自噬率。NLRP3缺乏还降低了血清促卵泡生成素和雌二醇水平。与这些结果一致，使用直接的NLRP3抑制剂MCC950对NLRP3进行药理学抑制，可将雌性小鼠的生育能力提高到与年轻小鼠相当的水平。这些结果表明，NLRP3炎性小体与女性生育能力随年龄增长的丧失有关，并将该炎性小体定位为治疗不孕症的潜在新治疗靶点。
