IL‐1 Receptor Blockade Prevents Fetal Cortical Brain Injury but Not Preterm Birth in a Mouse Model of Inflammation‐Induced Preterm Birth and Perinatal Brain Injury

Abstract

Problem Exposure to intrauterine inflammation, associated with preterm birth, has been linked to a devastating spectrum of neurobehavioral disorders. Mechanisms of this injury are unknown. Using a mouse model of intrauterine inflammation, we have observed a disruption of fetal neuronal morphology along with a marked elevation of Interleukin (IL)-1β in the fetal brain and placenta. In the current study, we hypothesized that IL-1 plays a key role in perinatal brain injury. Method of Study Utilizing a mouse model of inflammation-induced preterm birth, we investigated the role of IL-1 in fetal cortical injury as well as preterm birth. In these studies, dams received systemic treatment with IL-1 receptor antagonist prior to administration of intrauterine inflammation. Results Systemic maternal antagonism of IL-1 improved fetal cortical neuronal injury associated with the exposure to intrauterine inflammation, without affecting the phenotype of preterm birth. IL-1 receptor antagonist blocked activation of neuronal nitric oxide synthase in perinatal cortex, a key enzyme implicated in neurotoxicity. Conclusion Our data suggest that fetal cortical brain injury and preterm birth may occur by divergent mechanisms. Furthermore, our studies indicate maternal administration of IL-1 receptor antagonist (IL-1RA) blocked neuronal nitric oxide synthase activation observed in the brain cortex and, we speculate, that this alteration in activation leads to demonstrated decreased neurotoxicity.

Novel Noncompetitive IL-1 Receptor–Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth

“…Overall, our findings on the role of IL-1 concur with those previously reported by authors of this paper (17,77). Small biased ligands offer therapeutic advantages, which cannot be mimicked by currently available orthosteric inhibitors.…”

“…The abdominal muscle layer was sutured, and the skin was closed with clips. A total of 100 mL 101.10 (1 mg/Kg/12 h), Kineret (4 mg/Kg/12 h), SR-11302 (1 mg/Kg/12 h), Y27632 (0.5 mg/Kg/12 h), or vehicle was injected s.c. in the neck 30 min before stimulation with IL-1b, LPS, or LTA (to allow distribution of drugs to target tissues, in line with a first efficacy preclinical study); all doses used were based on reported efficacy (17,24,25,28,29). Mice delivery was assessed every hour until term (G19-G19.5).…”

“…IL-1-targeting agents reveal modest efficacy (16)(17)(18). At present there are three large molecule anti-IL-1 drugs approved for clinical use, as follows: the IL-1R antagonist Anakinra (Kineret), the soluble decoy receptor Rilonacept (Arcalyst), and the neutralizing anti-IL-1b mAb Canakinumab (Ilaris).…”

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…53,54 Since IL-1β has the potential to be damaging, its regulation is tightly controlled. Indeed, IL-1β is an important mediator of preterm birth 102,103,104,105 , and perinatal brain injury, 106,107,108,109 and can trigger the production of other pro-inflammatory cytokines and chemokines through the IL-1 receptor in a similar manner to TLRs. 55 Indeed delivery of a synthetic peptide to pregnant mice that is a selective IL-1 receptor modulator, delays IL-1β delays and LPS-induced preterm birth.…”

“…Indeed, a TLR4 antagonist prevented LPS-induced preterm uterine contractility in non-human primates 100 and knockout mice for TLR or associated adapter proteins are resistant to microbial and PAMP-induced preterm birth. 83,101 Similarly, since IL-1β is a mediator of preterm birth 102,103,104,105 and fetal brain injury 106,107,108,109 studies have focused on using IL-1 receptor antagonists or selective IL-1 receptor modulators to prevent these adverse outcomes. 110,111 Thus, preventing the upstream induction of IL-1β by inhibiting placental inflammasome activity may also serve as a potential target for preventing adverse pregnancy outcomes.…”