Inhibition of the NLRP3 inflammasome prevents ovarian aging

José M. 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

doi:10.1126/sciadv.abc7409

Inhibition of the NLRP3 inflammasome prevents ovarian aging

José M. 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

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103 Scopus citations

Abstract

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.

Original language	English
Article number	eabc7409
Journal	Science Advances
Volume	7
Issue number	1
DOIs	https://doi.org/10.1126/sciadv.abc7409
State	Published - Jan 1 2021

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Navarro-Pando, J. M., Alcocer-Gómez, E., Castejón-Vega, B., Navarro-Villarán, E., Condés-Hervás, M., Mundi-Roldan, M., Muntané, J., Pérez-Pulido, A. J., Bullon, P., Wang, C., Hoffman, H. M., Sanz, A., Mbalaviele, G., Ryffel, B., & Cordero, M. D. (2021). Inhibition of the NLRP3 inflammasome prevents ovarian aging. Science Advances, 7(1), Article eabc7409. https://doi.org/10.1126/sciadv.abc7409

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title = "Inhibition of the NLRP3 inflammasome prevents ovarian aging",

abstract = "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-M{\"u}llerian 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.",

author = "Navarro-Pando, {Jos{\'e} M.} and El{\'i}sabet Alcocer-G{\'o}mez and Beatriz Castej{\'o}n-Vega and Elena Navarro-Villar{\'a}n and M{\'o}nica Cond{\'e}s-Herv{\'a}s and Mar{\'i}a Mundi-Roldan and Jordi Muntan{\'e} and P{\'e}rez-Pulido, {Antonio J.} and Pedro Bullon and Chun Wang and Hoffman, {Hal M.} and Alberto Sanz and Gabriel Mbalaviele and Bernhard Ryffel and Cordero, {Mario D.}",

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year = "2021",

month = jan,

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Navarro-Pando, JM, Alcocer-Gómez, E, Castejón-Vega, B, Navarro-Villarán, E, Condés-Hervás, M, Mundi-Roldan, M, Muntané, J, Pérez-Pulido, AJ, Bullon, P, Wang, C, Hoffman, HM, Sanz, A, Mbalaviele, G, Ryffel, B & Cordero, MD 2021, 'Inhibition of the NLRP3 inflammasome prevents ovarian aging', Science Advances, vol. 7, no. 1, eabc7409. https://doi.org/10.1126/sciadv.abc7409

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AU - Navarro-Pando, José M.

AU - Alcocer-Gómez, Elísabet

AU - Castejón-Vega, Beatriz

AU - Navarro-Villarán, Elena

AU - Condés-Hervás, Mónica

AU - Mundi-Roldan, María

AU - Muntané, Jordi

AU - Pérez-Pulido, Antonio J.

AU - Bullon, Pedro

AU - Wang, Chun

AU - Hoffman, Hal M.

AU - Sanz, Alberto

AU - Mbalaviele, Gabriel

AU - Ryffel, Bernhard

AU - Cordero, Mario D.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - 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.

AB - 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.

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Inhibition of the NLRP3 inflammasome prevents ovarian aging

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