The Influence of Pentraxin 3 on the Ovarian Function and Its Impact on Fertility

Abstract

Follicular development is a highly coordinated process that in humans takes more than 6 months. Pituitary gonadotropins and a variety of locally produced growth factors and cytokines are involved in determining a precise sequence of changes in cell metabolism, proliferation, vascularization, and matrix remodeling in order to obtain a follicle with full ovulatory and steroidogenic capability. A low-grade inflammation can alter such processes leading to premature arrest of follicular growth and female reproductive failure. On the other hand, factors that are involved in inflammatory response as well as in innate immunity are physiologically upregulated in the follicle at the final stage of maturation and play an essential role in ovulation and fertilization. The generation of pentraxin 3 (PTX3) deficient mice provided the first evidence that this humoral pattern recognition molecule of the innate immunity has a non-redundant role in female fertility. The expression, localization, and molecular interactions of PTX3 in the periovulatory follicle have been extensively studied in the last 10 years. In this review, we summarize findings demonstrating that PTX3 is synthesized before ovulation by cells surrounding the oocyte and actively participates in the organization of the hyaluronan-rich provisional matrix required for successful fertilization. Data in humans tend to confirm these findings, indicating PTX3 as a biomarker of oocyte quality. Moreover, we discuss the emerging evidence that in humans altered PTX3 systemic levels, determined by genetic variations and/or low-grade chronic inflammation, can also impact the growth and development of the follicle and affect the incidence of ovarian disorders.

Keywords: PCOS; PTX3; cumulus matrix; fertility; follicle growth; ovarian disorders; theca cells.

Figure 1

Schematic representation of molecular interactions and functions of PTX3 during folliculogenesis. SNP haplotypes of PTX3 and altered circulating PTX3 levels in reproductive disorders suggest a role of PTX3 in the control of ovarian immune milieu during follicle development. In the preovulatory follicle, PTX3 is expressed by CCs and interacts with IαI and TSG6 for organizing the HA matrix, which is essential for oocyte ovulation and fertilization. After ovulation, PTX3 is expressed by stromal and endothelial cells of the corpus luteum and, by sequestering FGF2, is involved in vasculature involution during its regression. (CCs, cumulus cells; GCs, granulosa cells).

Figure 2

Proposed model of PTX3/HC/TSG6/HA interactions in cumulus matrix. During cumulus matrix formation, the binding of HA-linked HCs to the multimeric PTX3 molecule allows the crosslinking of several HA strands. TSG6, that catalyzes the transfer of HCs from CS of IαI to HA through the formation of an intermediate complex (TSG6-HC), also binds to PTX3. These interactions facilitate the simultaneous and coordinated integration of HCs and PTX3 within the cumulus matrix. (CS, chondroitin sulfate; LC, light chain; HC, heavy chain; HA, hyaluronan).