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

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

doi:10.1038/s41598-018-30087-4

Abstract

Antenatal inflammation as seen with chorioamnionitis is harmful to foetal/neonatal organ development including to eyes. Although the major pro-inflammatory cytokine IL-1β participates in retinopathy induced by hyperoxia (a predisposing factor to retinopathy of prematurity), the specific role of antenatal IL-1β associated with preterm birth (PTB) in retinal vasculopathy (independent of hyperoxia) is unknown. Using a murine model of PTB induced with IL-1β injection in utero, we studied consequent retinal and choroidal vascular development; in this process we evaluated the efficacy of IL-1R antagonists. Eyes of foetuses exposed only to IL-1β displayed high levels of pro-inflammatory genes, and a persistent postnatal infiltration of inflammatory cells. This prolonged inflammatory response was associated with: (1) a marked delay in retinal vessel growth; (2) long-lasting thinning of the choroid; and (3) long-term morphological and functional alterations of the retina. Antenatal administration of IL-1R antagonists – 101.10 (a modulator of IL-1R) more so than Kineret (competitive IL-1R antagonist) – prevented all deleterious effects of inflammation. This study unveils a key role for IL-1β, a major mediator of chorioamnionitis, in causing sustained ocular inflammation and perinatal vascular eye injury, and highlights the efficacy of antenatal 101.10 to suppress deleterious inflammation.

Highlights

Antenatal inflammation as seen with chorioamnionitis is harmful to foetal/neonatal organ development including to eyes
The major pro-inflammatory cytokine IL-1β participates in retinopathy induced by hyperoxia, the specific role of antenatal IL-1β associated with preterm birth (PTB) in retinal vasculopathy is unknown
To discriminate the specific role of antenatal IL-1β on oculo-vascular development we studied the effects of gestational IL-1β associated with foetal inflammatory response on development of retinal and choroidal vessels

Summary

Introduction

Antenatal inflammation as seen with chorioamnionitis is harmful to foetal/neonatal organ development including to eyes. The major pro-inflammatory cytokine IL-1β participates in retinopathy induced by hyperoxia (a predisposing factor to retinopathy of prematurity), the specific role of antenatal IL-1β associated with preterm birth (PTB) in retinal vasculopathy (independent of hyperoxia) is unknown. To discriminate the specific role of antenatal IL-1β (independent of hyperoxia - a predisposing factor to ROP) on oculo-vascular development we studied the effects of gestational IL-1β associated with foetal inflammatory response on development of retinal and choroidal vessels. Our findings reveal an important role for antenatal IL-1β, a major mediator of chorioamnionitis, in causing prolonged ocular inflammation in the offspring resulting in damage to retinal and sub-retinal vasculature, structure and function; these deleterious effects were prevented by antenatal 101.10 to a greater extent than Kineret

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