Elevated plasma and cerebrospinal fluid interleukin-1 beta and tumor necrosis factor-alpha concentration and combined outcome of death or abnormal neuroimaging in preterm neonates with early-onset clinical sepsis

Basu, Sriparna; Agarwal, Poojan; Anupurba, Shampa; Shukla, Ram Chandra; Kumar, Ashwani

doi:10.1038/jp.2015.86

Cited by 38 publications

(31 citation statements)

References 46 publications

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“…To date, there is no therapeutic molecule available to prevent/ alleviate pathological inflammatory processes in pregnant women at risk for PTB. Of all mediators implicated in gestational inflammation and the onset of neonatal morbidities, IL-1, which is a potent pleiotropic cytokine central to numerous inflammatory processes and capable of mounting an acute inflammatory response via ubiquitously expressed IL-1R, exerts a major detrimental role, as suggested by a broad body of evidence, including: 1) increased levels of IL-1b and IL-1Ra are early markers of neonatal injuries of the lung, intestine, and brain (21)(22)(23)(24), and such injuries can be recreated in rodent and ovine models via overexpression or administration of IL-1 (25)(26)(27); 2) antagonism of the IL-1 receptor, IL-1b, or inhibition of the cleavage and release of IL-1b by targeting caspase-1 activity provides improvement in outcomes of perinatal injuries to the aforementioned organs, including when triggered by upstream proinflammatory stressors (17,19,(28)(29)(30)(31)(32); and 3) inflammatory concentrations of IL-1b elicit neuromicrovascular decay (33), curtail hippocampal neuron differentiation (34), and consequently lead to seizures wherein IL-1b further contributes to brain injury (35). Therefore, IL-1 represents a target of high interest and potential to improve health outcomes in premature infants.…”

Section: Weeks From Acceptance To Publicationmentioning

confidence: 99%

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

Nadeau-Vallée

Chin

Belarbi

et al. 2017

The Journal of Immunology

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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.

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Section: Weeks From Acceptance To Publicationmentioning

confidence: 99%

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

Nadeau-Vallée

Chin

Belarbi

et al. 2017

The Journal of Immunology

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“…Infections account for 20%‐30% of all causes of preterm birth and are a well‐known cause of inflammation‐induced fetal brain injury 13‐23 . The remaining preterm births and fetal brain injuries have no detectable infectious origin, suggesting that inflammation may be involved 24‐27 …”

Section: Introductionmentioning

confidence: 99%

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

Chudnovets

Lei

et al. 2020

American J Rep Immunol

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Problem Systemic maternal inflammation is associated with adverse neonatal sequelae. We tested the hypothesis that IL‐1β is a key inflammatory regulator of adverse pregnancy outcomes. Method of study Pregnant mice were treated with intraperitoneal injections of IL‐1β (0, 0.1, 0.5, or 1 μg) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL‐1β signaling markers. Results As compared with non‐treated dams, maternal injections with IL‐1β resulted in increased p‐NF‐κB and caspase‐1 in placentas and fetal brains, but not consistently in spleens, suggesting induction of intrinsic IL‐1β production. These findings were confirmed by increased levels of IL‐1β in the placentas of the IL‐1β‐treated dams. Systemic treatment of dams with IL‐1β suppressed Stat1 signaling. Maternal inflammation caused by IL‐1β treatment reduced fetal viability to 80.6% and 58.9%, in dams treated with either 0.5 or 1 μg of IL‐1β, respectively. In the placentas, there was an IL‐1β dose‐dependent distortion of the labyrinth structure, decreased numbers of mononuclear trophoblast giant cells, and reduced proportions of endothelial cells as compared to placentas from control dams. In fetal brains collected at E17, there was an IL‐1β dose‐dependent reduction in cortical neuronal morphology. Conclusion This work demonstrates that systemic IL‐1β injection causes dose‐dependent structural and functional changes in the placenta and fetal brain.

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“…A large number of immune effector cells are mobilized into the neonatal circulation [1–3]. Concomitantly, these immune cells release proinflammatory cytokines such as tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) which readily cross the blood-brain barrier into the brain parenchyma [4]. In the latter, the serum-derived proinflammatory cytokines can activate microglia, the resident immune cells in the central nervous system (CNS), which initiates complex inflammatory cascades including excessive release of proinflammatory cytokines, reactive oxygen species (ROS), and glutamate excitotoxicity [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats

Han

Lin

Huang

et al. 2017

J Neuroinflammation

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BackgroundAxon development plays a pivotal role in the formation of synapse, nodes of Ranvier, and myelin sheath. Interleukin-1β (IL-1β) produced by microglia may cause myelination disturbances through suppression of oligodendrocyte progenitor cell maturation in the septic neonatal rats. Here, we explored if a microglia-derived IL-1β would disturb axon development in the corpus callosum (CC) following lipopolysaccharide (LPS) administration, and if so, whether it is associated with disorder of synapse formation in the cerebral cortex and node of Ranvier.MethodsSprague-Dawley rats (1-day old) in the septic model group were intraperitoneally administrated with lipopolysaccharide (1 mg/kg) and then sacrificed for detection of IL-1β, interleukin-1 receptor (IL-1R1), neurofilament-68, neurofilament-160, and neurofilament-200, proteolipid, synaptophysin, and postsynaptic density 95 (PSD95) expression by western blotting and immunofluorescence. Electron microscopy was conducted to observe alterations of axonal myelin sheath and synapses in the cortex, and proteolipid expression was assessed using in situ hybridization. The effect of IL-1β on neurofilament and synaptophysin expression in primary neuron cultures was determined by western blotting and immunofluorescence. P38-MAPK signaling pathway was investigated to determine whether it was involved in the inhibition of IL-1β on neurofilament and synaptophysin expression.ResultsIn 1-day old septic rats, IL-1β expression was increased in microglia coupled with upregulated expression of IL-1R1 on the axons. The expression of neurofilament-68, neurofilament-160, and neurofilament-200 (NFL, NFM, NFH) and proteolipid (PLP) was markedly reduced in the CC at 7, 14, and 28 days after LPS administration. Simultaneously, cortical synapses and mature oligodendrocytes were significantly reduced. By electron microscopy, some axons showed smaller diameter and thinner myelin sheath with damaged ultrastructure of node of Ranvier compared with the control rats. In the cerebral cortex of LPS-injected rats, some axo-dendritic synapses appeared abnormal looking as manifested by the presence of swollen and clumping of synaptic vesicles near the presynaptic membrane. In primary cultured neurons incubated with IL-1β, expression of NFL, NFM, and synaptophysin was significantly downregulated. Furthermore, p38-MAPK signaling pathway was implicated in disorder of axon development and synaptic deficit caused by IL-1β treatment.ConclusionsThe present results suggest that microglia-derived IL-1β might suppress axon development through activation of p38-MAPK signaling pathway that would contribute to formation disorder of cortical synapses and node of Ranvier following LPS exposure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0805-x) contains supplementary material, which is available to authorized users.

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Elevated plasma and cerebrospinal fluid interleukin-1 beta and tumor necrosis factor-alpha concentration and combined outcome of death or abnormal neuroimaging in preterm neonates with early-onset clinical sepsis

Abstract: Elevation of plasma and CSF IL-1β and TNF-α is associated with an increase in the combined outcome of death or abnormal neuroimaging in preterm neonates with EOCS in the absence of clinical/microbiological evidence of meningitis with high predictive accuracy.

Cited by 38 publications

References 46 publications

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

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

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

Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats

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