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

Cardoso FL, Herz J, Fernandes A, Rocha J, Sepodes B, Brito MA, McGavern DB, Brites D - J Neuroinflammation (2015)

Bottom Line: However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known.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.Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels.

View Article: PubMed Central - PubMed

Affiliation: Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003, Lisbon, Portugal. filipacardoso@ff.ulisboa.pt.

ABSTRACT

Background: The 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).

Methods: Systemic 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 CX3CR1(gfp/+) mice combined with cryo-immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes.

Results: LPS 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.

Conclusion: Collectively, 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.

No MeSH data available.


Related in: MedlinePlus

Early lipopolysaccharide (LPS) administration causes transient body and brain weight loss and decreases the cerebellar area. (A) Body and brain of CD1 wild-type mice were weighed at 1 and 9 days post-LPS administration. (B) Body weight of C57BL/6 (B6) CX3CR1gfp/+ mice was assessed at days 1/3/5/7/9 after LPS injection. (C) Cerebellar area was measured in tiled confocal images of brain sections from B6 CX3CR1gfp/+ mice at days 1/3/5/7/9 post-LPS (representative images with DAPI in (D). Results are mean ± SEM from at least four animals. **P < 0.01 vs. without (W/O) LPS.
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Fig2: Early lipopolysaccharide (LPS) administration causes transient body and brain weight loss and decreases the cerebellar area. (A) Body and brain of CD1 wild-type mice were weighed at 1 and 9 days post-LPS administration. (B) Body weight of C57BL/6 (B6) CX3CR1gfp/+ mice was assessed at days 1/3/5/7/9 after LPS injection. (C) Cerebellar area was measured in tiled confocal images of brain sections from B6 CX3CR1gfp/+ mice at days 1/3/5/7/9 post-LPS (representative images with DAPI in (D). Results are mean ± SEM from at least four animals. **P < 0.01 vs. without (W/O) LPS.

Mentions: Administration of LPS is known to induce a sickness behavior in adult mice, including weight loss [55,56]. To assess the impact of LPS exposure in the first postnatal week, we initially assessed body and brain weight oscillations, which were acutely decreased by LPS (Figure 2A). Body weight loss was sustained up to LPS7 (P < 0.01) but eventually recovered by LPS9 (Figure 2B). We further explored acute brain weight loss by measuring the sagittal cerebellar area. This revealed a disruption in its development evidenced by an approximately twofold reduction at LPS5 that was still evident at LPS7 (P < 0.01). No difference from the control group was observed at LPS9 (Figure 2C,D).Figure 2


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

Cardoso FL, Herz J, Fernandes A, Rocha J, Sepodes B, Brito MA, McGavern DB, Brites D - J Neuroinflammation (2015)

Early lipopolysaccharide (LPS) administration causes transient body and brain weight loss and decreases the cerebellar area. (A) Body and brain of CD1 wild-type mice were weighed at 1 and 9 days post-LPS administration. (B) Body weight of C57BL/6 (B6) CX3CR1gfp/+ mice was assessed at days 1/3/5/7/9 after LPS injection. (C) Cerebellar area was measured in tiled confocal images of brain sections from B6 CX3CR1gfp/+ mice at days 1/3/5/7/9 post-LPS (representative images with DAPI in (D). Results are mean ± SEM from at least four animals. **P < 0.01 vs. without (W/O) LPS.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4440597&req=5

Fig2: Early lipopolysaccharide (LPS) administration causes transient body and brain weight loss and decreases the cerebellar area. (A) Body and brain of CD1 wild-type mice were weighed at 1 and 9 days post-LPS administration. (B) Body weight of C57BL/6 (B6) CX3CR1gfp/+ mice was assessed at days 1/3/5/7/9 after LPS injection. (C) Cerebellar area was measured in tiled confocal images of brain sections from B6 CX3CR1gfp/+ mice at days 1/3/5/7/9 post-LPS (representative images with DAPI in (D). Results are mean ± SEM from at least four animals. **P < 0.01 vs. without (W/O) LPS.
Mentions: Administration of LPS is known to induce a sickness behavior in adult mice, including weight loss [55,56]. To assess the impact of LPS exposure in the first postnatal week, we initially assessed body and brain weight oscillations, which were acutely decreased by LPS (Figure 2A). Body weight loss was sustained up to LPS7 (P < 0.01) but eventually recovered by LPS9 (Figure 2B). We further explored acute brain weight loss by measuring the sagittal cerebellar area. This revealed a disruption in its development evidenced by an approximately twofold reduction at LPS5 that was still evident at LPS7 (P < 0.01). No difference from the control group was observed at LPS9 (Figure 2C,D).Figure 2

Bottom Line: However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known.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.Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels.

View Article: PubMed Central - PubMed

Affiliation: Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003, Lisbon, Portugal. filipacardoso@ff.ulisboa.pt.

ABSTRACT

Background: The 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).

Methods: Systemic 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 CX3CR1(gfp/+) mice combined with cryo-immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes.

Results: LPS 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.

Conclusion: Collectively, 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.

No MeSH data available.


Related in: MedlinePlus