Antenatal Suppression of IL-1 Protects against Inflammation-Induced Fetal Injury and Improves Neonatal and Developmental Outcomes in Mice

Abstract

Preterm birth (PTB) is commonly accompanied by in utero fetal inflammation, and existing tocolytic drugs do not target fetal inflammatory injury. Of the candidate proinflammatory mediators, IL-1 appears central and is sufficient to trigger fetal loss. Therefore, we elucidated the effects of antenatal IL-1 exposure on postnatal development and investigated two IL-1 receptor antagonists, the competitive inhibitor anakinra (Kineret) and a potent noncompetitive inhibitor 101.10, for efficacy in blocking IL-1 actions. Antenatal exposure to IL-1β induced ,, ,, and expression in placenta and fetal membranes, and it elevated amniotic fluid IL-1β, IL-6, IL-8, and PGF, resulting in PTB and marked neonatal mortality. Surviving neonates had increased ,, ,, ,, and expression in WBCs, elevated plasma levels of IL-1β, IL-6, and IL-8, increased IL-1β, IL-6, and IL-8 in fetal lung, intestine, and brain, and morphological abnormalities: e.g., disrupted lung alveolarization, atrophy of intestinal villus and colon-resident lymphoid follicle, and degeneration and atrophy of brain microvasculature with visual evoked potential anomalies. Late gestation treatment with 101.10 abolished these adverse outcomes, whereas Kineret exerted only modest effects and no benefit for gestation length, neonatal mortality, or placental inflammation. In a LPS-induced model of infection-associated PTB, 101.10 prevented PTB, neonatal mortality, and fetal brain inflammation. There was no substantive deviation in postnatal growth trajectory or adult body morphometry after antenatal 101.10 treatment. The results implicate IL-1 as an important driver of neonatal morbidity in PTB and identify 101.10 as a safe and effective candidate therapeutic.

Recent advances in the prevention of preterm birth

“…Studies using the commercially available antagonist Kineret have been overshadowed by a new, allosteric peptide IL-1R antagonist known as rytvela 136 . Rytvela treatment in pregnant mice improved fetal and neonatal outcomes following exposure to either IL-1β or LPS 136– 138 , blocked uterine/placental/intra-amniotic inflammation, and prevented myometrial activation, PTB, fetal demise, and inflammation-related morbidities; rytvela-exposed pups exhibited overtly normal growth and development 137, 138 . In all studies, rytvela equalled or outperformed Kineret, despite being used at lower doses.…”

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

“…These UAPs promote cervical ripening, fetal membrane weakening, contractions and labor [34][35][36]. Importantly, data show that this inflammatory response does not resolve with birth [16], which may explain the inefficacy of tocolytics at improving neonatal outcomes. Interleukin (IL)-1β is a key pro-inflammatory cytokine that has been strongly linked to PTB [37].…”

“…Calcium channel blockers, specifically nifedipine, have also been shown to have fewer side effects and a lower neonatal morbidity rate [15]. However, nifedipine is associated with higher rates of adverse effects in women with cardiovascular disease, congenital cardiac malformations or pulmonary hypertension [15,16].…”

“…In murine models (hemochorial placentation akin to humans), the intrauterine inflammatory response has been shown to reach the fetal compartment, possibly though a cytokine chain reaction. This induces severe injuries to the fetal organs that begin in utero and persist into adulthood [16]. The inflammatory response begins with bacteria or stressed cells that induce release of small motives (Pathogen/Danger-Associated Molecular Patterns) that are recognized by Toll-like receptors (TLR; receptors part of the innate immune system) expressed throughout gestational tissues.…”

“…More recently, a small all-d peptide, 101.10, was designed to partially inhibit IL-1RI without blocking important pathways for cytoprotection [70]. Pre-clinical murine studies have been tremendously promising, as it prevents PTB and protects the fetus from multisystemic perinatal injuries [16,71]. This encouraging finding indicates IL-1β is a good pharmacological target to curb inflammation at the beginning of its cascade, therefore protecting the fetus from inflammation-associated damages.…”