Interleukin-1 blockade attenuates white matter inflammation and oligodendrocyte loss after progressive systemic lipopolysaccharide exposure in near-term fetal sheep

Journal of Neuroinflammation

Laura Bennet¹  Justin M. Dean¹  Alistair J. Gunn¹  Valerie A. Zahra²  Alison Moxham²  Vanesa Stojanovska²  Timothy J. M. Moss²  Sharmony B. Kelly³  Stuart B. Hooper³  Graeme R. Polglase³  Robert Galinsky³  Suzanne L. Miller³  Claudia A. Nold-Petry⁴  Marcel F. Nold⁵ 

[1] Department of Physiology, The University of Auckland, Auckland, New Zealand;The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright street, 3168, Melbourne, Victoria, Australia;The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright street, 3168, Melbourne, Victoria, Australia;Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia;The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright street, 3168, Melbourne, Victoria, Australia;Department of Paediatrics, Monash University, Melbourne, Victoria, Australia;The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright street, 3168, Melbourne, Victoria, Australia;Department of Paediatrics, Monash University, Melbourne, Victoria, Australia;Monash Newborn, Monash Children’s Hospital, Melbourne, Australia;

关键词: Inflammation;    Brain;    Interleukin-1;   

DOI  :  10.1186/s12974-021-02238-4

来源: Springer

【 摘 要 】

BackgroundIncreased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS).MethodsChronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n = 9). Sheep were euthanized 4 days after starting infusions for histology.ResultsLPS infusions increased circulating cytokines and were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P < 0.05 vs. control for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and caspase-3+ cells, and improved olig-2+ oligodendrocyte survival.ConclusionIL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.

【 授权许可】

CC BY