Involvement of neuronal IL-1β in acquired brain lesions in a rat model of neonatal encephalopathy

Journal of Neuroinflammation

Guillaume Sebire²  Denis Gris²  Martin Lepage¹  Djordje Grbic²  Marie-Elsa Brochu²  Karine Lavoie²  Alexandre Savard² 

[1] Département de Médecine Nucléaire et Radiobiologie, Université de Sherbrooke, Sherbrooke, Québec, Canada;Département de Pédiatrie, Université de Sherbrooke, Sherbrooke, Québec, Canada

关键词: Inflammation;    Pathogen exposure;    Term newborn;    Hypoxia-ischemia;   

Others  :  1152134
DOI  :  10.1186/1742-2094-10-110

 received in 2013-06-12, accepted in 2013-08-21,  发布年份 2013

【 摘 要 】

Background

Infection-inflammation combined with hypoxia-ischemia (HI) is the most prevalent pathological scenario involved in perinatal brain damage leading to life-long neurological disabilities. Following lipopolysaccharide (LPS) and/or HI aggression, different patterns of inflammatory responses have been uncovered according to the brain differentiation stage. In fact, LPS pre-exposure has been reported to aggravate HI brain lesions in post-natal day 1 (P1) and P7 rat models that are respectively equivalent - in terms of brain development - to early and late human preterm newborns. However, little is known about the innate immune response in LPS plus HI-induced lesions of the full-term newborn forebrain and the associated neuropathological and neurobehavioral outcomes.

Methods

An original preclinical rat model has been previously documented for the innate neuroimmune response at different post-natal ages. It was used in the present study to investigate the neuroinflammatory mechanisms that underline neurological impairments after pathogen-induced inflammation and HI in term newborns.

Results

LPS and HI exerted a synergistic detrimental effect on rat brain. Their effect led to a peculiar pattern of parasagittal cortical-subcortical infarcts mimicking those in the human full-term newborn with subsequent severe neurodevelopmental impairments. An increased IL-1β response in neocortical and basal gray neurons was demonstrated at 4 h after LPS + HI-exposure and preceded other neuroinflammatory responses such as microglial and astroglial cell activation. Neurological deficits were observed during the acute phase of injury followed by a recovery, then by a delayed onset of profound motor behavior impairment, reminiscent of the delayed clinical onset of motor system impairments observed in humans. Interleukin-1 receptor antagonist (IL-1ra) reduced the extent of brain lesions confirming the involvement of IL-1β response in their pathophysiology.

Conclusion

In rat pups at a neurodevelopmental age corresponding to full-term human newborns, a systemic pre-exposure to a pathogen component amplified HI-induced mortality and morbidities that are relevant to human pathology. Neuronal cells were the first cells to produce IL-1β in LPS + HI-exposed full-term brains. Such IL-1β production might be responsible for neuronal self-injuries via well-described neurotoxic mechanisms such as IL-1β-induced nitric oxide production, or IL-1β-dependent exacerbation of excitotoxic damage.

【 授权许可】

   
2013 Savard et al.; licensee BioMed Central Ltd.

【 图 表 】

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