Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects

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.

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

“…cDNA synthesis was performed using the RT 2 First Strand Kit (Qiagen) followed by quantitative RT-PCR (qRT-PCR) using the CFX96 Touch Real-Time PCR Detection System (Bio-Rad Laboratories) with RT 2 SYBR Green qPCR Master Mix (Qiagen). cDNA samples from each time point were screened with RT 2 Profiler PCR Array Rat NFκB Signaling Pathway (Qiagen). Data were analyzed using the SABiosciences PCR Array Data Analysis Web Portal (www.…”

“…pulsed focused ultrasound | microbubbles | blood-brain barrier | sterile inflammation | magnetic resonance imaging T he temporal proteomic profile in response to blood-brain barrier disruption (BBBD) consists of molecular features that are common across noninfectious insults such as ischemia, trauma, or autoimmune diseases (1)(2)(3)(4)(5)(6)(7). The main purpose of the bloodbrain barrier (BBB) is to maintain homeostasis, preventing the passive crossing of cells and molecules that could induce inflammation or damage to cells.…”

Neonatal Lipopolysaccharide Infection Causes Demyelination and Behavioral Deficits in Adult and Senile Rat Brain

“…Both developing and mature neurons and glia possess numerous pro-inflammatory cytokine receptors, which make them susceptible to inflammation-assocaited damage [14] . The neuroinflammatory response was reported to occur with weight loss [15,16] , neurodegeneration [17] , white matter damage [18], and cognitive and affective disorder [19] . Since LPS can reproduce many of the neuroinflammatory complications, it has been considered as the most established animal model for investigating the impact of bacterial-induced neuroinflammation [12,17,20] .…”

“…The neuroinflammatory response was reported to occur with weight loss [15,16] , neurodegeneration [17] , white matter damage [18], and cognitive and affective disorder [19] . Since LPS can reproduce many of the neuroinflammatory complications, it has been considered as the most established animal model for investigating the impact of bacterial-induced neuroinflammation [12,17,20] . Demyelination induced by bacteria can be studied by analyzing the molecular changes in the unique myelin axonal proteins like proteolipid protein, myelin basic protein, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein (MOG) [7] .…”

Toll-like receptor (TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications

“…TLR-2 and TLR-4 are abundantly expressed in various neurons, including the cortical and dorsal neurons, and trigeminal nerves (Fernandez-Lizarbe et al, 2013;Cardoso et al, 2015). Bi et al (2014) and Rosenberger et al (2014) proposed that alternations in the expression of TLR-2/4 may regulate the proliferation and growth of neurons, and the inflammatory response.…”