Antenatal IL-1-dependent inflammation persists postnatally and causes retinal and sub-retinal vasculopathy in progeny

Beaudry-Richard, Alexandra; Nadeau-Vallée, Mathieu; Prairie, Élizabeth; Maurice, Noémie; Heckel, Émilie; Nezhady, Mohammad Ali Mohammad; Pundir, Sheetal; Madaan, Ankush; Boudreault, Amarilys; Hou, Xin; Quiniou, Christiane; Sierra, Estefania Marin; Beaulac, Alexandre; Lodygensky, Gregory A.; Robertson, Sarah A.; Keelan, Jeffrey A.; Waldorf, Kristina M. Adams; Olson, David M.; Rivera, Jose-Carlos; Lubell, William D.; Joyal, Jean‐Sébastien; Bouchard, Jean‐François; Chemtob, Sylvain

doi:10.1038/s41598-018-30087-4

Cited by 26 publications

(27 citation statements)

References 73 publications

(115 reference statements)

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“…Current ROP treatments employ anti-vascular endothelial growth factor (VEGF) antibodies and laser photocoagulation (Hellström et al, 2013) which treat the proliferative phase of the disease but fail to address earlier stage vaso-obliteration and associated inflammation. Modulation of IL-1R signaling offers the potential to mitigate both PTB and ROP as indicated by the in vivo results herein and previously reported (Rivera et al, 2013; Nadeau-Vallée et al, 2015, 2017; Beaudry-Richard et al, 2018).…”

Section: Discussionsupporting

confidence: 70%

Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constraint of Peptide-Based Interleukin-1 Receptor Biased Ligands

et al. 2019

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Interleukin-1β (IL-1β) binds to the IL-1 receptor (IL-1R) and is a key cytokine mediator of inflammasome activation. IL-1β signaling leads to parturition in preterm birth (PTB) and contributes to the retinal vaso-obliteration characteristic of oxygen-induced retinopathy (OIR) of premature infants. Therapeutics targeting IL-1β and IL-1R are approved to treat rheumatoid arthritis; however, all are large proteins with clinical limitations including immunosuppression, due in part to inhibition of NF-κB signaling, which is required for immuno-vigilance and cytoprotection. The all-D-amino acid peptide 1 (101.10, H- d -Arg- d -Tyr- d -Thr- d -Val- d -Glu- d -Leu- d -Ala-NH 2 ) is an allosteric IL-1R modulator, which exhibits functional selectivity and conserves NF-κB signaling while inhibiting other IL-1-activated pathways. Peptide 1 has proven effective in experimental models of PTB and OIR. Seeking understanding of the structural requirements for the activity and biased signaling of 1 , a panel of twelve derivatives was synthesized employing the various stereochemical isomers of α-amino-γ-lactam (Agl) and α-amino-β-hydroxy-γ-lactam (Hgl) residues to constrain the D-Thr-D-Val dipeptide residue. Using circular dichroism spectroscopy, the peptide conformation in solution was observed to be contingent on Agl, Hgl, and Val stereochemistry. Moreover, the lactam mimic structure and configuration influenced biased IL-1 signaling in an in vitro panel of cellular assays as well as in vivo activity in murine models of PTB and OIR. Remarkably, all Agl and Hgl analogs of peptide 1 did not inhibit NF-κB signaling but blocked other pathways, such as JNK and ROCK2 phosphorylation contingent on structure and configuration. Efficacy in preventing preterm labor correlated with a capacity to block IL-1β-induced IL-1β synthesis. Furthermore, the importance of inhibition of JNK and ROCK2 phosphorylation for enhanced activity was highlighted for prevention of vaso-obliteration in the OIR model. Taken together, lactam mimic structure and stereochemistry strongly influenced conformation and biased signaling. Selective modulation of IL-1 signaling was proven to be particularly beneficial for curbing inflammation in models of preterm labor and retinopathy of prematurity (ROP). A class of biased ligands has been created with potential to serve as selective probes for studying IL-1 signaling in disease. Moreover, the small peptide mimic prototypes are promising leads for developing immunomodulatory therapies with easier administration and maintenance of beneficial effects of NF-κB signaling.

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Section: Discussionsupporting

confidence: 70%

Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constraint of Peptide-Based Interleukin-1 Receptor Biased Ligands

et al. 2019

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“…Recent evidences showed that choroidal thinning is present in adolescents and adults formerly affected with ROP (Wu et al, 2013;Erol et al, 2016;Rivera et al, 2017b). Similarly, our group also detected a sustained choroidal thinning in different animal models of ROP (Shao et al, 2011;Zhou et al, 2016;Beaudry-Richard et al, 2018). To date, several studies have focused their effort in developing novel anti-angiogenic monotherapy against the aberrant NV, by using anti-growth factors such as anti-VEGF, -FGF, -IGF and their receptors (Cabral et al, 2017).…”

Section: Introductionsupporting

confidence: 73%

MicroRNA-96 Promotes Vascular Repair in Oxygen-Induced Retinopathy—A Novel Uncovered Vasoprotective Function

et al. 2020

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Background and Aims: Vascular degeneration is a hallmark in the pathogenesis of oxygen-induced retinopathy (OIR). Dysregulation of microRNAs (miRNAs), key regulators of genes expressions, has been implicated in the regulation of ocular angiogenesis. However, miRNAs specific functions in impaired vascular development during OIR are poorly understood. Herein, we identified miR-96 as one of the most highly expressed miRNAs in the retina and choroid during vascular development and investigated the potential role of miR-96 on microvascular degeneration in a rat OIR model. Methods and Results: Next generation sequencing (NGS) and qRT-PCR analysis showed that miR-96 maintain high levels of expression during ocular vascular development. Nevertheless, miR-96 was significantly downregulated in the retina and choroid of OIR rats (80% O 2 from P5 to P10) during the phase of microvascular degeneration. Similarly, human retinal microvascular endothelial cells (HRMEC) subjected to hyperoxia (80% O 2) showed a significant downregulation of miR-96 evaluated by qPCR. Interestingly, HRMEC supplemented with miR-96 regulated positively the expression of several key angiogenic factors including VEGF and ANG-2. To explore the angiogenic activity of miR-96 on HRMEC, we performed a gain/loss of function study. In a similar way to hyperoxia exposure, we observed a robust angiogenic impairment (tubulogenesis and migration) on HRMEC transfected with an antagomiR-96. Conversely, overexpression of miR-96 stimulated the angiogenic activity of HRMEC and protected against hyperoxia-induced endothelial dysfunction. Finally, we evaluated the potential vasoprotective function of miR-96 in OIR animals. Rat pups intravitreally supplemented with miR-96 mimic (1 mg/kg) displayed a significant preservation of retinal/choroidal microvessels at P10 compared to controls. This result was consistent with the maintenance of physiologic levels of VEGF and ANG-2 in the OIR retina. Conclusion: This study demonstrates that miR-96 regulates the expression of angiogenic factors (VEGF/ANG-2) associated to the maintenance of retinal and choroidal microvasculature during physiological and pathological conditions. Intravitreal

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“…As a result, early inflammation should be regarded as a main risk factor for ROP. However, the mechanism of early inflammation that triggers detrimental effects in the retina during ROP is still unclear and such inflammation is difficult to evaluate and predict .…”

Section: Discussionmentioning

confidence: 99%

Algorithm for predicting threshold retinopathy of prematurity is insufficient and fundus examinations are still needed before 31 weeks

Wirth

Naud

Caputo³

et al. 2018

Acta Paediatrica

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Aim: We evaluated the weight, insulin-like growth factor-1, neonatal, retinopathy of prematurity (WINROP) algorithm for very premature infants.Method: Infants born before 32 weeks who had undergone fundus examinations in the neonatal intensive care unit at the University Hospital of Nancy were included in this French retrospective cohort study from July 2012 to July 2016. We evaluated how well the WINROP software predicted threshold retinopathy of prematurity (ROP).Results: We studied 570 infants with a mean gestational age of 28.7 AE 1.8 weeks and a mean birth weight of 1110 AE 297 g: 28.1% had ROP and 1.2% had threshold ROP. The overall WINROP sensitivity was 57.1%, specificity was 46.0%, predictive positive value was 1.3% and predictive negative value was 98.9%. At more than 30 weeks of gestation or 1250 g, these figures rose to a respective specificity of 100% and 95.7% and respective predictive negative value of 100% and 100%. There were independent associations between the severity of ROP and the Apgar score at five minutes, the duration of oxygen therapy and non-invasive ventilation.Conclusion: WINROP worked better on preterm infants born from 31 weeks onwards or weighing over 1250 g. Fundus examinations remain necessary for infants born earlier or lighter.

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Antenatal IL-1-dependent inflammation persists postnatally and causes retinal and sub-retinal vasculopathy in progeny

Cited by 26 publications

References 73 publications

Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constraint of Peptide-Based Interleukin-1 Receptor Biased Ligands

Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constraint of Peptide-Based Interleukin-1 Receptor Biased Ligands

MicroRNA-96 Promotes Vascular Repair in Oxygen-Induced Retinopathy—A Novel Uncovered Vasoprotective Function

Algorithm for predicting threshold retinopathy of prematurity is insufficient and fundus examinations are still needed before 31 weeks

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