P2X7 receptor blockade prevents preterm birth and perinatal brain injury in a mouse model of intrauterine inflammation†

Abstract

The P2X7 is an adenosine triphosphate (ATP)-gated ion channel involved in several facets of immune activation and neuronal function through its importance in interleukin (IL)-1β secretion. We hypothesized that blockade of P2X7 would prevent perinatal brain injury associated with exposure to intrauterine (IU) inflammation. Dams received 45 mg/kg of Brilliant Blue G (BBG), a specific P2X7 receptor (P2X7R) antagonist, on gestation day 17 (E17) prior to administration of lipopolysaccharide (LPS) or phosphate-buffered saline (PBS). Furthermore, we utilized embryo transfer experiments to delineate whether the P2X7 was the key mediator of IU inflammation-associated brain injury on maternal or fetal sides. In these experiments, P2X7-/- dams were embryo-transferred wild type embryos and wild type dams were embryo-transferred P2X7-/- embryos. In the mouse model of intrauterine inflammation, pharmacologic blockade of P2X7R reduced preterm birth rate, improved offspring performance on neuromotor tests as well as the dendritic arborization and density of cortical neurons. Embryo transfer experiments demonstrated the importance of maternal P2X7R in IU inflammation-mediated effects on offspring. Both genetic and pharmacologic blockade of IL-1β signaling, by targeting maternal P2X7R, ameliorated perinatal brain injury following exposure to IU inflammation. Specific targeting of maternal P2X7R may provide a clinically useful tool to prevent both preterm birth and prematurity-associated perinatal brain injury, and further studies are urgently needed.

Dose‐dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy

“…To test whether maternal treatment with rIL‐1β causes changes in fetal viability, viable and aborted fetuses were quantified as previously done in mouse models of maternal infection 34,35,48 . Fetal viability was significantly reduced following maternal treatment with either 0.5 or 1 µg, but not 0.1 µg, of rIL‐1β as compared with PBS‐treated dams ( P < .05, χ 2 ; Figure 1A).…”

“…Furthermore, this inflammatory response induces passage of cytokines and chemokines to the fetal brain, generating local immune response and further activation of the immune system of the fetus 34,35,71 . Of all the cytokines implicated, IL‐1β stands out, as the main mediator of perinatal brain injury and it directly and indirectly induces neurotoxicity, 23,72 whereas its blockage using pharmacological and genetic methods exerts neuroprotective effects in animal studies 9,48,73‐75 …”

“…The response to maternal inflammation is marked by increased expression of proinflammatory cytokines, such as IL1‐β, IL‐6, and tumor necrosis factor (TNF)‐α, in both placental and fetal tissues 36‐41 . IL‐1β, in particular, may mediate inflammation in the placenta to cause fetal neurotoxicity and long‐term perinatal sequelae 34,35,42‐48 …”

P2X7 receptors drive poly(I:C) induced autism-like behavior in mice

“…Interestingly, we could not detect significant change in IL-1␤ levels in response to MIA in either P2rx7 ϩ/ϩ or P2rx7 Ϫ/Ϫ animals, which argues against the activation of the canonical P2rx7-IL-1␤-NLRP3 signaling pathway, at least at this early time point. Consistently, maternal P2rx7 inhibition, but not IL-1␤ blockade, was effective to prevent preterm birth and neonatal brain injury in a mouse model of perinatal intrauterine inflammation (Tsimis et al, 2017). Nevertheless, it cannot be excluded that at later time points other cytokines and soluble mediators also participated in maternal and fetal response to poly(I:C)-induced endogenous P2rx7 activation.…”

IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection

“…Previous studies employing intrauterine LPS have established that IL-1β-mediated inflammation in the maternal compartment and placenta predicts the extent of fetal neurotoxicity and long-term adverse perinatal sequelae (56)(57)(58)(59). Furthermore, IL-1 receptor blockade with IRA decreases activation of neuronal NOS (nNOS), cortical neuronal cell death, and perinatal brain injury, all of which occur with exposure to intrauterine inflammation (25,60,61). Intraperitoneal injections of murine recombinant IL-1β (rIL-1β) during E15-E17 of gestation result in neurologic sequelae (62), consistent with ZIKV (the present study) and LPS (56,(63)(64)(65), illustrating that elevated IL-1β during pregnancy is a significant mediator of adverse perinatal outcomes.…”