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

Abstract

BackgroundInfection-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.MethodsAn 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.ResultsLPS 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.ConclusionIn 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.

Label-Free LC–MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis

“…The latter three processes are similar to those recently identified using microarray analysis of gene expression in oculomotor and spinal motor neurons 81 , while elevations in inflammation-associated proteins, specifically those of the complement pathway, have been previously associated with human ALS 70, 82–84 and ALS model systems 85, 86 . We detect elevations in several proteins of the complement pathway, confirming previously-described elevations of CSF C3 70,82 and providing new evidence for an increase in C5 (which is upregulated in animal models of ALS 85, 87 ) and C2, as well as decreased complement factor I. Our results support a role of elevated complement pathway activation as a contributing factor to motor neuron death and a potential therapeutic target.…”

Neuroprotective effects of hypothermia in inflammatory‐sensitized hypoxic‐ischemic encephalopathy

“…Using the same model of inflammatory‐sensitized HI, we previously showed that the IL‐1/TNF‐α/MMP‐9 inflammatory axis was upregulated from 4 h to 24 h post‐HI, and played a key role in LPS + HI‐induced brain injuries (Savard et al, 2015, 2013). Thus, in the present study, we tested the influence of HT on the expression of these key neurotoxic molecules.…”

“…We previously showed that IL‐1β played a key role: (i) in the early (4–24 h) LPS + HI‐induced neuroinflammatory response, and (ii) in generating both core and penumbra cerebral injuries of NE (Savard et al, 2015, 2013). In the present study, HT acted only on penumbra but not on core of LPS + HI‐induced brain lesions of term‐like newborns.…”

Perinatal Arterial Ischemic Stroke Is Associated to Materno-Fetal Immune Activation and Intracranial Arteritis

“…Rats were placed on their back, four paws in the air. The time to move from paws in the air to four paws on the ground was measured and the pups were classified as having an impaired righting reflex when the delay to achieve a full righting reflex was more than 1 s. In the Elevated Body Swing Test (EBST) P16 rats were held by the base of the tail head downwards during 20 s, as previously described [42,46]. The number of effective upswings (+90°) and the total number of upswing were compared between the S + PT + H and LPS + PT + H groups.…”