NLRP14 deficiency causes female infertility with oocyte maturation defects and early embryonic arrest by impairing cytoplasmic UHRF1 abundance.

Oocyte maturation is vital to attain full competence required for fertilization and embryogenesis. NLRP14 is preferentially expressed in mammalian oocytes and early embryos. Yet, the role and molecular mechanism of NLRP14 in oocyte maturation and early embryogenesis are poorly understood, and whether NLRP14 deficiency accounts for human infertility is unknown. Here, we found that maternal loss of Nlrp14 resulted in sterility with oocyte maturation defects and early embryonic arrest (EEA). Nlrp14 ablation compromised oocyte competence due to impaired cytoplasmic and nuclear maturation. Importantly, we revealed that NLRP14 maintained cytoplasmic UHRF1 abundance by protecting it from proteasome-dependent degradation and anchoring it from nuclear translocation in the oocyte. Furthermore, we identified compound heterozygous NLRP14 variants in women affected by infertility with EEA, which interrupted the NLRP14-UHRF1 interaction and decreased UHRF1 levels. Our data demonstrate NLRP14 as a cytoplasm-specific regulator of UHRF1 during oocyte maturation, providing insights into genetic diagnosis for female infertility.

The TH 22-mediated IL-22 deficiency associated with premature ovarian insufficiency.

RESEARCH QUESTION: Is deficiency of IL-22 associated with premature ovarian insufficiency (POI)? DESIGN: Levels of IL-22 and IL-22BP, IL-22-producing T cells, and IL22RA1/IL10R2 expression were measured and compared among 29 patients with POI, 42 with precursor stage of POI (pre-POI) and 46 control women. Correlation of serum IL-22 and IL-22+ CD4+ T subsets with ovarian reserve markers were further analyzed. RESULTS: IL-22 levels in serum significantly differed among control women and patients with pre-POI and POI, with the lowest concentrations in POI group (p = .019). Significant reduction of peripheral CD4+ IL-22+ T cells was observed in patients with POI (p = .010), which mainly contributed by decrease of CD4+ IL-22+ IL-17- TH 22 cells (p = .012) but not TH 17 cells (p = .125). Levels of serum IL-22 and IL-22-producing CD4+ T subsets were significantly correlated with ovarian reserve markers, including AMH, bilateral AFC, follicle-stimulating hormone (FSH), and E2 (p < .05). The specific receptor IL22RA1 expression was marginally reduced in granulosa cells from patients with pre-POI (p = .051). No difference of IL-22BP was observed either in serum (p = .216) or follicular fluid (p = .856) among groups. CONCLUSIONS: Our study first demonstrated the significant association between TH 22-mediated IL-22 deficiency and ovarian insufficiency, which provide new insights into the autoimmune disturbance and opens new avenues for exogenous IL-22 administration as potential intervention of POI.

The Impact of Moderately High Preconception Thyrotropin Levels on Ovarian Reserve Among Euthyroid Infertile Women Undergoing Assisted Reproductive Technology.

Background: Thyroid dysfunction is prevalent in reproductive-age women and has been identified as a risk factor for female infertility. However, it remains largely unclear whether subtle thyroid dysfunction, as estimated by moderately high thyrotropin (TSH) levels within the normal range, is associated with ovarian reserve in infertile women before assisted reproductive technology (ART) treatment. Methods: This cross-sectional study involved 3501 euthyroid infertile women, including 2189 women with TSH levels ≤2.5 µIU/mL and 1312 women with high-normal TSH levels (2.51-4.20 µIU/mL). Ovarian reserve markers were compared between women with low- and high-normal TSH levels. Correlation analysis and regression models were used to estimate the association of TSH levels with ovarian reserve. In addition, the association of subtle thyroid dysfunction with ovarian reserve was further evaluated after stratification for different infertility diagnoses and statuses of thyroid autoimmunity (TAI). Results: In the total population, women with high-normal TSH levels had significantly decreased anti-Müllerian hormone (AMH) concentrations (p < 0.001), a lower bilateral antral follicle count (AFC) (p < 0.001), and a higher prevalence of diminished ovarian reserve (DOR) (p = 0.018) than women with low-normal TSH levels. The TSH levels showed a negative association with both AMH levels (r = -0.050, p = 0.003) and bilateral AFC (r = -0.071, p < 0.001). Furthermore, the association of high-normal TSH levels with decreased AMH and AFC was more prominent in infertile women with ovulation dysfunction (p = 0.002, p = 0.002), unexplained infertility (p = 0.020, p = 0.028), or negative TAI (both p < 0.001). Conclusions: These data suggested that subtle thyroid dysfunction was associated with DOR in infertile women before ART treatment, which will add evidence that strengthens the systematic screening of TSH levels/TAI in infertile women and will contribute to the discussion of specific TSH cutoff values in predicting ovarian reserve.

Two distinct resident macrophage populations coexist in the ovary.

Introduction: Tissue-resident macrophages (TRMs) are highly heterogeneous and have a complex and important role in tissue support, homeostasis, and function. The heterogeneity, maintenance, and function of TRMs, as one of the major immune cells in the ovary, are not well understood. Methods: Application of flow cytometry, Parabiosis, Fate mapping, Macrophage depletion, etc. Results: Here, we described two distinct macrophage subsets, F4/80hiCD11bint and F4/80intCD11bhi, with different phenotypic characteristics in the ovary of mice. The F4/80hiCD11bint population contained a distinct CD206+ subgroup and highly expressed CD81, while the F4/80intCD11bhi subset showed higher expression of CCR2 and TLR2. Notably, Ly6c+ macrophages were present almost exclusively in the F4/80intCD11bhi subpopulation. Combining in vivo fate mapping and parabiotic mouse models, we characterized the longevity and replenishment of the two macrophage populations. We found that both the F4/80hiCD11bint and F4/80intCD11bhi subsets were ovary-resident. Importantly, the F4/80hiCD11bint macrophages acted as a self-maintaining and long-lived population with a modest monocyte contribution at a steady state, and the F4/80intCD11bhi subpopulation had a relatively short lifespan with a greater contribution from monocytes. After macrophage ablation, disturbance of estradiol secretion and ovarian hemorrhage due to damaged vascular integrity was observed in mice. Discussion: Our data provide critical insights into ovarian macrophage heterogeneity and highlight the strategic role of TRMs in ovarian homeostasis and physiology.