Novel Biomarker for Ascending Placentitis: IL-6
The broodmare is the cornerstone of the breeding industry, and immense effort, countless hours and considerable finances go into the delivery of a healthy foal. While achieving a viable pregnancy is a hurdle in itself, maintaining that pregnancy to term is the primary concern of practitioners, breeders and managers alike.
In North America, the leading cause of equine abortion is the ascending migration of bacteria through the cervix to localize on the placenta. The inflammation/infection that this causes is deemed ascending placentitis, and this disease results in the loss of 3-5% of all pregnancies. Currently, ascending placentitis is diagnosed based on clinical alterations, including vaginal discharge alongside premature mammary gland development and lactation. Additionally, practitioners may rely on trans-rectal ultrasonography, where an increase in placental thickness at the caudal pole of the cervix may be indicative of placental inflammation. Unfortunately, many of these alterations occur late in the disease process, resulting in a delay in therapeutic interference. Because of this, considerable work has gone into the detection of biomarkers that can be accessible in a noninvasive sampling procedure, sensitive for the early detection of inflammation/infection, and specific for the disease of ascending placentitis.
Recently, the cytokine interleukin-6 (IL-6) was found to be a novel biomarker for this disease, with a sensitivity of 97% and a specificity of 75%. This discovery will soon be published in the American Journal of Reproductive Immunology in the article “Interleukin-6 Pathobiology in Equine Placental Infection,” with Carleigh Fedorka, PhD, postdoctoral fellow at the University of Kentucky Gluck Equine Research Center as the lead investigator. The research will also be presented at a December conference sponsored by the American Association of Equine Practitioners.
Although considerable differences exist when comparing horses to humans, pregnant women sometimes experience a similar disease to that of ascending placentitis, and this is known as intra-amniotic infection (IAI; chorioamnionitis). The gold standard diagnostic for IAI is an elevated IL-6 concentration within amniotic fluid, although this cytokine is also elevated in cervical fluid, vaginal fluid and within circulation. IL-6 is a pleiotropic cytokine, and therefore can function as both pro- and anti-inflammatory due to its ability to activate varying receptors and different pathways. In the horse, IL-6 protein has been found to increase in both amniotic fluid and allantoic fluid during ascending placentitis, in addition to increasing within both fetal and maternal tissues following the experimental induction of this disease. Unfortunately, fetal fluid sampling is rarely used in veterinary practice due to concerns for iatrogenic abortion.
In contrast, the present study found IL-6 to increase in circulation; indicating a safe, sensitive and specific sampling method for the prediction of ascending placentitis.
This was further expanded utilizing transcriptomics and immunolabeling to determine that IL-6 was activating the IL-6 receptor (IL-6R) via the classical signaling pathway. This activation of the JAK/STAT pathway is proposed to lead to various downstream effects, including an inhibition of apoptosis, epithelial cell proliferation and anti-inflammatory outcomes. Additionally, this is the first paper to report that the IL-6R was expressed in the equine placenta, indicating a paracrine signaling pathway between the equine fetus and mare.
Future research is needed to determine the utility of this biomarker in the field. It is believed that the naturally occurring disease of ascending placentitis is more chronic to that of the experimental model, and therefore the IL-6 response may differ. Additionally, it is unknown if this anti-inflammatory pathway is altered preceding abortion in comparison to the delivery of a viable neonate. This is an obvious next step in the research, alongside investigating alterations in IL-6 concentrations in other pregnancy-related complications, including nocardioform placentitis, leptospirosis and idiopathic abortions.
Carleigh Fedorka, PhD, Postdoctoral Fellow at the UK Gluck Equine Research Center, provided this information.