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-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.

Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950

“…Inflammation detrimentally affects reproductive physiology and female fertility. In a recent study (Navarro-Pando et al, 2021) NLRP3 was found to be increased in the ovary of aged mice. Increased expression of NLRP3 and other key downstream markers, caspase-1 and IL-1b, were also detected in granulosa cells from patients with primary ovarian insufficiency.…”

Leptin Signaling in the Ovary of Diet-Induced Obese Mice Regulates Activation of NOD-Like Receptor Protein 3 Inflammasome

“…We presently observed not only a similar pattern of cellular expression for NLRP3 but also the upregulation of NLRP3 inflammasome components during D. These findings corroborate previous results from Zhang and colleagues suggesting the involvement of NLRP3 in inflammatory events during ovulation in mice ( Zhang et al, 2019 ). Moreover, NLRP3 was recently characterized as an important mediator of ovarian pathology during aging ( Navarro-Pando et al, 2021 ). Finally, the involvement of NLRP3 inflammasome in ovarian inflammatory response in obese mothers is supported by previous reports showing NLRP3 inflammasome activation in proinflammatory conditions like PCOS ( Wang et al, 2017 ; Guo et al, 2020 ).…”

Autophagy in major human diseases

“…Dysfunctional autophagy has also been linked to ovarian insufficiency due to inflammatory aging and miscarriage, as well as to male infertility. For example, inhibition of the NLRP3 inflammasome leads to increased levels of autophagy markers in the ovary of 12‐month‐old female mice and is linked to improved reproductive pregnancy rate (Navarro‐Pando et al , 2021 ), whereas pharmacological induction of autophagy (by rapamycin) promotes endometrium autophagy (and NK cell infiltration), thus decreasing the risk of spontaneous abortion in mice (Lu et al , 2020 ). In addition, functional autophagy sustains correct spermiogenesis.…”