Inhibition of the NLRP3 inflammasome prevents ovarian aging

José Manuel Navarro-Pando; Elísabet Alcocer-Gómez; Beatriz Castejón-Vega; Elena Navarro-Villarán; Mónica Condés-Hervás; María Mundi-Roldan; Jordi Muntané; Antonio J. Pérez-Pulido; Pedro Bullon; Chun Wang; Hal M. Hoffman; Alberto Sanz; Gabriel Mbalaviele; Bernhard Ryffel; Mario D. Cordero

Resumen:

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 Nlrp3−/− 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.