Abstract
Background
Endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects 10% of women of reproductive age. Ovarian endometriosis (OE) is the most common lesion in endometriosis and may cause infertility in addition to dysmenorrhea. Hormonal treatments for endometriosis suppress ovulation; hence, they are not compatible with fertility. The inflammasome is a complex that includes Nod-like receptor (NLR) family proteins that sense pathogen-/danger‐associated molecular patterns and homeostasis-altering molecular processes. It has been reported that the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3 inflammasome, which contributes to the activation of interleukin-1 beta (IL-1β), might be related to the progression of endometriosis. Therefore, the aim of the present study was to evaluate non-hormonal therapies for OE, such as the inhibitors of the NLRP3 inflammasome.
Methods
The expression of NLRP3 was measured in the eutopic endometrium (EM) of patients with/without endometriosis and OE and stromal cells derived from the endometrium of patients with endometriosis and OE (endometrial stromal cells [ESCs] and cyst-derived stromal cells [CSCs]). The effect of an NLRP3 inhibitor (MCC950) on ESC and CSC survival and IL-1β production was evaluated. We then administered MCC950 to a murine model of OE to evaluate its effects on OE lesions and ovarian function.
Results
NLRP3 gene and protein expression levels were higher in OE and CSCs than in EM and ESCs, respectively. MCC950 treatment significantly reduced the survival of CSCs but not that of ESCs. Moreover, MCC950 treatment reduced the co-localization of NLRP3 and IL-1β in CSCs and IL-1β concentrations in CSC supernatants. In the murine model, MCC950 treatment reduced OE lesion size compared to phosphate-buffered saline treatment (89 ± 15 vs. 49 ± 9.3 mm3 per ovary; P < 0.05). In addition, IL-1β and Ki67 levels in the OE-associated epithelia and oxidative stress markers of granulosa cells were reduced in the MCC950-treated group.
Conclusions
These results indicate that NLRP3/IL-1β is involved in the pathogenesis of endometriosis and that NLRP3 inhibitors may be useful for suppressing OE and improving the function of ovaries with endometriosis.
