Placentitis, or inflammation/infection of the placenta, is a primary cause of abortion in horses. This disease contributes to roughly 25% of all infectious abortions, having immense economic impact on the breeding industry [1,2]. Prevalence and etiology of this disease varies based on breeding locale, but the primary etiology is that of the ascending migration of bacteria (S. equi subs. zooepidemicus, Escherichia coli, Pseudomonas aeruginosa) through the cervical canal to localize on the cervical pole of the placenta. Ascending placentitis is a significant contributor of fetal loss in North America [[2], [3], [4]], Europe [[5], [6], [7], [8], [9]], and Australasia [10,11]. Gold standard diagnostics for this disease relies on clinical alterations of the mare, including premature mammary gland development, vaginal/vulvar discharge, and transcrectal ultrasonography to measure the combined thickness of the uterus and placenta (CTUP) alongside separation noted between the chorion and endometrium [12,13] (Fig. 1).

The initial pathophysiology of ascending placentitis is believed to begin with the ascending migration of bacteria through the vagina and cervical canal to infect both maternal and fetal tissues that are spatially adjacent to the cervix [14]. Host detection of pathogen has been proposed to activate various cell types, including the columnar epithelial cells of the uterus, decidual macrophages, and the eventual activation of both innate and adaptive immune cells types, such as neutrophils, monocytes, and lymphocytes. This process is believed to be initiated by the maternal production of various pro-inflammatory cytokines (IL-1β, IL-8) in addition to arachidonic acid metabolites (PGF2α, PGE2), leading to a rapid and acute inflammatory response [14,15]. The inflammation appears to be isolated to the reproductive tract, as no increase in maternal temperature or alteration in peripheral white blood cell count is noted [16]. Recent research has indicated that the following immune response can be deviated into two different disease processes – that of acute or chronic placentitis. Acute placentitis is governed by pro-inflammatory mediators, with minimal anti-inflammatory or immunomodulatory signaling occurring from either mare or feto-placental unit. Due to this pro-inflammatory signaling, the trigger mechanism for parturition/abortion is delivered, and the fetus is rapidly expelled. This is noted in the experimental model and occurs anywhere between 2 and 25 days after inoculation [14,16,17]. In contrast, many mares experience a chronic placentitis in which the feto-placental unit responds to the maternal pro-inflammatory signaling with anti-inflammatory feedback, specifically in the cytokine production of anti-inflammatory IL-10 and pleiotropic IL-6 [18]. It is known that the equine fetus is able to produce lymphocytes as early as 60 days of gestation, is responsive to viral infection by 230 days of gestation, and is in constant cross talk with the mare between maternal Tregs and fetal B cell production throughout pregnancy [[19], [20], [21]]. Therefore, an increase in fetal IL-6 and IL-10 leads us to hypothesize that the fetus is having an antenatal response to the disease process of ascending placentitis and is responding to the pro-inflammatory signaling derived from the mare to combat this trigger for parturition/abortion.

Recent research has prioritized areas of focus to better understand the pathophysiology of this disease. One primary focus has been on the use of bioinformatics alongside RNA sequencing to garner a broader archetype of the pathways altered during disease progress. Secondly, various tissues have been included within this bioinformatic analysis to gain a more comprehensive representation of the feto-maternal response to disease. Thirdly, the effect of various immunomodulators have been evaluated for efficacy as mediators of inflammation. And finally, considerable attention has been paid to the detection of biomarkers for this disease, both in invasive and noninvasive sampling procedures. In this narrative review, we will discuss our basic understanding of the pathophysiology of equine placentitis, with a focus on the immune response to the disease. To garner this information, a comprehensive literature search of peer-reviewed literature was performed on the topic of ascending infectious placental disease in the horse, and manuscripts of high quality and intact scientific methodology were included within this synopsis. With a better understanding of etiology, we can make inferences into advanced detection of placentitis, in addition to provide therapeutics to diminish the consequences of infection/inflammation within the feto-placental unit.