Abstract
The pathogenesis of inflammation in the central nervous system (CNS), which contributes to numerous neurodegenerative diseases and results in encephalopathy and neuroinflammation, is poorly understood. Sphingolipid metabolism plays a crucial role in maintaining cellular processes in the CNS, and thus mediates the various pathological consequences of inflammation. For a better understanding of the role of sphingosine kinase activation during neuroinflammation, we developed a bacterial lipopolysaccharide (LPS)-induced brain injury model. The onset of the inflammatory response was observed beginning 4 hours after intracerebral injection of LPS into the lateral ventricles of the brain. A comparison of established neuroinflammatory parameters such as white matter rarefactions, development of cytotoxic edema, astrogliosis, loss of oligodendrocytes, and major cytokines levels in wild type and knockout mice suggested that the neuroinflammatory response in SphK1−/− mice was significantly upregulated. At 6 hours after intracerebroventricular injection of LPS in SphK1−/− mice, the immunoreactivity of the microglia markers and astrocyte marker glial fibrillary acidic protein (GFAP) were significantly increased, while the oligodendrocyte marker O4 was decreased compared to WT mice. Furthermore, western blotting data showed increased levels of GFAP. These results suggest that SphK1 activation is involved in the regulation of LPS induced brain injury.Research Highlights• Lipopolysaccharide (LPS) intracerebral injection induces severe neuroinflammation. • Sphingosine kinase 1 deletion worsens the effect of the LPS. • Overexpression of SphK1 might be a potential new treatment approach to neuroinflammation.
Highlights
The inflammatory response starts with recognition of viral or bacterial products and typically plays a defensive role [1,2], but when these mechanisms are overactive the evoked cascade can be fatal [3]
Intracerebral injection of LPS in TLR42/2 mice did not result in neutrophil activation [13], and mice lacking this receptor were hyporesponsive to LPS in general [14]
Hematoxylin and eosin (H&E) stained coronal brain sections were carefully studied under light microscope for any pathological changes
Summary
The inflammatory response starts with recognition of viral or bacterial products and typically plays a defensive role [1,2], but when these mechanisms are overactive the evoked cascade can be fatal [3]. During neuroinflammation as a first line of defense, the innate immune system recognizes a limited number of invading pathogens. It has been shown that LPS binding to toll-like receptors (TLR’s) and clusters of differentiation (CD11 and CD14) [2] activates a variety of immune cells such as monocytes, macrophages, leukocytes and neutrophils. In the mammalian immune system, lipopolysaccharide is recognized by toll-like receptor-4 (TLR4) [12]. Intracerebral injection of LPS in TLR42/2 mice did not result in neutrophil activation [13], and mice lacking this receptor were hyporesponsive to LPS in general [14]
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