Abstract
BackgroundThe inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice. However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known. Thus, we investigated the effects of repeated LPS administration in the first postnatal week in mice, a condition mimicking sepsis in late preterm infants, on the developing central nervous system (CNS).MethodsSystemic inflammation was induced by daily intraperitoneal administration (i.p.) of LPS (6 mg/kg) in newborn mice from postnatal day (PND) 4 to PND6. The effects on neurodevelopment were examined by staining the white matter and neurons with Luxol Fast Blue and Cresyl Violet, respectively. The inflammatory response was assessed by quantifying the expression/activity of matrix metalloproteinases (MMP), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1, and autotaxin (ATX). In addition, B6 CX3CR1gfp/+ mice combined with cryo-immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes.ResultsLPS administration led to acute body and brain weight loss as well as overt structural changes in the brain such as cerebellar hypoplasia, neuronal loss/shrinkage, and delayed myelination. The impaired myelination was associated with alterations in the proliferation and differentiation of NG2 progenitor cells early after LPS administration, rather than with excessive phagocytosis by CNS myeloid cells. In addition to disruptions in brain architecture, a robust inflammatory response to LPS was observed. Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels. Acute astrogliosis (GFAP+ cells) in the brain parenchyma and at the microvasculature interface together with parenchymal microgliosis (CX3CR1+ cells) were also observed. These changes preceded the migration/proliferation of CX3CR1+ cells around the vessels at later time points and the subsequent loss of GFAP+ astrocytes.ConclusionCollectively, our study has uncovered a complex innate inflammatory reaction and associated structural changes in the brains of neonatal mice challenged peripherally with LPS. These findings may explain some of the neurobehavioral abnormalities that develop following neonatal sepsis.
Highlights
The inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice
We found that sustained systemic inflammation interferes with central nervous system (CNS) maturation by causing neuronal atrophy, a delay in myelination, and acute reactive gliosis
Given that matrix metalloproteinases (MMP)-9 can open the blood-brain barrier (BBB) [89] and LPS induces its expression through the toll-like receptor 4 (TLR4)/NF-κB pathway [90], we investigated whether this receptor was upregulated after the LPS challenge
Summary
The inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice. Systemic administration of LPS, an endotoxin of gram-negative bacteria, is widely used to induce a neuroinflammatory response associated with short-term ‘sickness’ behavior [8] in adult [9] and newborn animals [10] as well as during gestation [11]. In these models, weight loss is a commonly observed sign of illness [12,13,14] and is one of the consequences of sepsis [15,16]. A single systemic LPS injection is intended to reproduce the acute systemic LPS-mediated inflammation [8], whereas a repetitive challenge is used to model a chronic condition [20,21]
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