The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes

Abstract

Introduction: Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes.Methods: Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb.Results: Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased NAMPT expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1–14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAb-induced reductions in inflammatory pathway genes.Discussion: The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPT-neutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates.

Extracellular Nicotinamide Phosphoribosyltransferase Is a Therapeutic Target in Experimental Necrotizing Enterocolitis

“…We have previously reported the effective use of the ALT-100 mAb in preclinical models of ARDS [51], radiation fibrosis [53], pulmonary hypertension [49,92], lupus vasculitis [54], NASH hepatic fibrosis and ischemia induced cardiac fibrosis [76], and chorioamnionitis [50]. Highly relevant to this study, in a preclinical pregnant mouse model of chorioamnionitis-related preterm birth (PTB), the ALT-100 mAb was shown to delay PTB, increase neonate survival, and reduce IAI-related PTB complications, including bronchopulmonary dysplasia and pulmonary hypertension [48].…”

“…We previously used genomic strategies and identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel DAMP and TLR4 ligand that potently initiates NF-κB transcription-dependent inflammatory responses and cytokine release [47]. We have shown that the eNAMPT/TLR4 inflammatory cascade is a druggable pathway in preclinical models of pulmonary hypertension [48][49][50], acute respiratory distress syndrome [51], radiation-induced lung disease [52,53], lupus vasculitis [54], and Crohn's disease [55,56].…”

Hydrogen gas inhalation ameliorates LPS-induced BPD by inhibiting inflammation via regulating the TLR4–NFκB–IL6/NLRP3 signaling pathway in the placenta

“…NF-κB is a downstream signaling linked by TLR4. LPS could directly induce TLR4 and activation of NF-κB signaling, which in turn led to production of inflammatory factors [ 36 , 37 ]. Given the role of TLR4/NF-κB signaling pathway in inflammation, we investigated the beneficial effect of inhaled H 2 on LPS-induced BPD, and we raised the question: does hydrogen inhibit inflammation by downregulating the expression of the hub protein TLR4 and subsequently reducing the activity of the NF-κB-mediated inflammatory signaling pathway?…”

Elevated expression of Toll-like receptor 4 and cytokines in both serum and myometrium at term may serve as promising biomarkers for uterine activation preceding labor

“…Toll-like receptors (TLRs) are crucial protein molecules involved in the body’s nonspecific immune response, acting as a bridge between terms innate and adaptive immunity ( 41 ). Current research indicates that TLR4 can promote preterm birth by upregulating the expression of pro-inflammatory factors and chemokines ( 42 ). Studies have shown similarities in the changes of white blood cells between infection-induced preterm labor and non-infected full-term labor, which can be attributed to the direct or indirect effects of TLR4 ( 43 ).…”