Persistent reduction in sialylation of cerebral glycoproteins following postnatal inflammatory exposure

Abstract

BackgroundThe extension of sepsis encompassing the preterm newborn’s brain is often overlooked due to technical challenges in this highly vulnerable population, yet it leads to substantial long-term neurodevelopmental disabilities. In this study, we demonstrate how neonatal neuroinflammation following postnatal E. coli lipopolysaccharide (LPS) exposure in rat pups results in persistent reduction in sialylation of cerebral glycoproteins.MethodsMale Sprague-Dawley rat pups at postnatal day 3 (P3) were injected in the corpus callosum with saline or LPS. Twenty-four hours (P4) or 21 days (P24) following injection, brains were extracted and analyzed for neuraminidase activity and expression as well as for sialylation of cerebral glycoproteins and glycolipids.ResultsAt both P4 and P24, we detected a significant increase of the acidic neuraminidase activity in LPS-exposed rats. It correlated with significantly increased neuraminidase 1 (Neu1) mRNA in LPS-treated brains at P4 and with neuraminidases 1 and 4 at P24 suggesting that these enzymes were responsible for the rise of neuraminidase activity. At both P4 and P24, sialylation of N-glycans on brain glycoproteins decreased according to both mass-spectrometry analysis and lectin blotting, but the ganglioside composition remained intact. Finally, at P24, analysis of brain tissues by immunohistochemistry showed that neurons in the upper layers (II–III) of somatosensory cortex had a reduced surface content of polysialic acid.ConclusionsTogether, our data demonstrate that neonatal LPS exposure results in specific and sustained induction of Neu1 and Neu4, causing long-lasting negative changes in sialylation of glycoproteins on brain cells. Considering the important roles played by sialoglycoproteins in CNS function, we speculate that observed re-programming of the brain sialome constitutes an important part of pathophysiological consequences in perinatal infectious exposure.

Complete Spatial Characterisation of N-glycosylation upon Striatal Neuroinflammation in the Rodent Brain

“…Only a few in vitro studies have been performed so far; however, all of them consistently describe a decrease in sialylation in in ammation models 33,34 . This reduction in sialylation was also seen in an LPS-injected post-natal rat model 35 . Nonetheless, only perinatal infectious exposure was considered, and only one glycosylation trait was analysed (sialylation).…”

“…It was seen that in all of these there were signi cant differences: a drastic decrease in sialylation (n=5, Paired Student's t-test, p<0. Sialylation and Fucosylation are the main traits dysregulated upon neuroin ammation General discrepancies in sialylation and fucosylation have been reported in CNS-impairments and neuroin ammatory scenarios 35,48 . Therefore, we looked further into these two features in the context of N-glycosylation (Figure 5).…”

Decreased Immunoglobulin G Core Fucosylation, A Player in Antibody-dependent Cell-mediated Cytotoxicity, is Associated with Autoimmune Thyroid Diseases

“…The glycosylation of IgGs and PBMCs was analyzed using biotinylated lectins in LB previously described (39). LB is also considered for quantitative analysis of glycosylation as described in previous studies (40,41). The lectin specificity was determined based on the glycoprotein reaction with lectins blocked by the inhibiting sugars or 200 mM acetic acid for 24h at 4°C.…”

Control of Innate Immunity by Sialic Acids in the Nervous Tissue

“…It has been shown that postnatal inflammatory exposure causes ultimate increase in the activity of the neuraminidases NEU1 and NEU4. This increased neuraminidase activity immediately resulted in desialylation of glycoproteins of neural cells [ 130 ]. Furthermore, oxidative damage has been shown to desialylate cell surfaces [ 131 ].…”