Dendritic Cells – Restrained During Ovulation
A new study published in Genes & Immunity may explain why some immune responses, and particularly dendritic cells (DCs) functions are restrained during ovulation.
The menstrual cycle is related to subtle changes in sex hormone levels (see Cover Image) that may have, however, profound effects on innate and adaptive immune responses.
Estradiol levels, which are low during the first half of the menstrual cycle, rise and peak 2–3 days before ovulation.
During ovulation, humoral and cell-mediated immune responses are believed to be suppressed in order to provide optimal conditions for procreation.
However, in the normal menstrual cycle, this may be related to a ‘window of vulnerability’ during the menstrual cycle beginning at ovulation and lasting 7–10 days. In this period the potential for viral infectivity in the female reproductive tract (FRT) is enhanced.
During that period, aspects of the innate, humoral, and cell-mediated immune systems are suppressed by sex hormones, and, thus, females are more susceptible to infections of the FRT, including Candida albicans, genital herpes simplex virus, Chlamydia trachomatis and HIV.
The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception. In the human FRT, sperm is ‘stored’ for many days, i.e. fertilization occurs when intercourse takes place up to 6 days before ovulation. Thus, a N Engl J Med study indicates that among healthy women trying to conceive
nearly all pregnancies can be attributed to intercourse during a six-day period ending on the day of ovulation.
Thus, the above-mentioned time-frame is also considered to be causally related to an ‘immune tolerance’ to the allogeneic sperm, and allows semen to survive during ovulation and during this ‘window of opportunity and tolerance’ to increase the chance of fertilization. This phenomenon and the overall hormonal control of FRT’s infections and reproductive functions remain unclear.
Dendritic cells (DCs) link innate immunity to adaptive immunity. Upon exposure to microbial invaders in tissue, they undergo a maturational process that culminates in the lymph nodes and activates T-cell-specific immune responses. Estradiol, which is highly expressed during ovulation, has an effect on the maturation of DCs, although the molecular mechanism remains elusive.
The biological actions of estrogen are mediated through association of the E2 receptor proteins with the estrogen-responsive elements (EREs) in the promoters of E2-regulated genes.
In the Genes & Immunity study S. Lasarte et al. from the Hospital General Universitario Gregorio Marañón, Madrid, Spain to further investigate the molecular mechanism by which E2 downregulates DC functions analyzed the expression of genes whose regulatory regions contain EREs, and provide new insights into these mechanisms.
The authors of this study demonstrate that estradiol is able to suppress the NF-κb translocation to the nucleus, a step crucial for the dendritic cells maturation process, by its transcriptional downregulation of Ikbkg expression at the promoter level in DCs.
Ikbkg is the regulatory subunit of the inhibitor of NF-kb kinase (IKK) complex. Nf-kb dimers remain inactive in the cytoplasm by association with Nfkbia. After stimulation, the IKK complex phosphorylates Nfkbia and undergoes proteasomal degradation.
Free Nf-kb can then translocate into the nucleus and stimulate the transcription of target genes. This translocation step is necessary for the promotion of the DC maturation program that induces migration and ends with the antigen presentation to the T cells in the lymph nodes.
The investigators found that detected estradiol regulates expression of Ikbkg in DCs and modulates nuclear factor-κb translocation to the nucleus. This change may be an adaptive mechanism to reconcile control of infection and reproductive functions.
This may explain the reduced DCs’ function observed during ovulation. The authors suggest that estradiol–inhibited DCs would not trigger the maturation program, migrate to the T-cell areas and upregulate antigen presentation proteins during estrus (high estradiol) so that spermatozoa can survive.
Therefore, allogeneic spermatozoa could reach and be stored at the oviduct in order to acquire the ability to fertilize. According to the authors
DCs are ‘shutdown’ due to this hormone-driven adaptive mechanism that may bring together the female immune response with reproductive function.
These findings may also be related to the inhibitory effects of estrus levels of estradiol on sperm-induced Th17 responses recently reported by the same research group.
Source: Genes Immun, 2013, 14:462-9. doi: 10.1038/gene.2013.35. Epub 2013 Jul 25.
Read More: Genes & Immunity
Updates
A 2014 study by Adva Cohen-Fredarow et al. demonstrated that CD11c-positive, F4/80-negative cells, apparently representing dendritic cells (DCs), reside in the ovary before ovulation. In response to the ovulatory stimulus provided by hCG, these cells gradually accumulate in the preovulatory follicles and overpopulate the newly formed corpus luteum. This study further provided evidence for the crucial role of these cells in ovulation. Specifically, we demonstrated that after the depletion of these cells ovulation failed.
The authors also showed that not only follicle rupture but also the formation of a functional corpus luteum is fully dependent on these DCs. Importantly, the study also suggests that these cells mediate the expression of a set of anti-inflammatory genes, apparently involved in the restraint of the physiologic ovulatory-associated inflammation.
The authors put forward the model for the role of DCs in ovulation. Upon gonadotropin stimulation, the relatively small ovarian DC population mediates the LH-stimulated up-regulation of specific genes, such as Tnfaip6, Vcan-V1, Star, Pgr, and Adamts1 that are essential for cumulus mucification/expansion and ovulation. As the ovulatory process progresses, the ovarian DC population expands and localizes to the corpus luteum to control the inflammatory conditions provoked by ovulation.
This activity is executed by suppressing proinflammatory factors such as Il6, Il1, Tnf, Ccl2, Egr1, and Cxcl2, which is secondary to up-regulation of the inflammatory repressing genes Adcyap1 and Tnfaip6. In the early luteal phase, the substantial amount of DCs localized in the newly formed corpus luteum facilitates progesterone production as well as ovarian lymphangiogenesis.
In a 2019 review Diane M Duffy et al. discussed in depth that inflammation triggered by pathogens or injury shares significant similarities with inflammation initiated by the LH surge in the ovulatory follicle. This observation led to the proposal that ovulation is, in itself, an inflammatory process. Upon LH stimulation, the ovary exhibits many classical signs of local inflammation: production of inflammatory mediators, increased blood flow, leukocyte infiltration, swelling, tissue digestion, and, ultimately, tissue repair.
Short historical perspective: More than 40 years ago Bukovsky and Presl proposed that the immune system regulated ovulatory ovarian function. In his landmark paper in 1980, Espey put forth the hypothesis of ovulation as an inflammatory reaction and outlined the similarities in inflammatory processes and ovulation.
The past three decades of investigation into the mechanism of ovulation have not only strengthened support for Espey’s view that ovulation is an inflammatory process but have also led to a better understanding of how the inflammatory process is regulated in the ovary. Many cells, gene products, and activities that contribute to LH-initiated ovulatory inflammation have been identified, and the roles they play have been illuminated.
In many ways these findings have supported Espey’s statement that “the intended question is whether the endocrine system might be operating, at least in those instances where gonadotropins stimulate their specific target tissues, by ‘taking advantage’ of the immunoresponsive capacity inherent in all cells in mammalian systems.”
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