Decreased sialylation in the mouse retina elicits complement-related microglia response and bipolar cell loss
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ABSTRACT:
PROVIDER: PRJNA1149053 | ENA |
REPOSITORIES: ENA
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Project description:Sialylation plays an important role in self-recognition, as well as keeping the complement and innate immune systems in check. It is unclear whether the reduced sialylation as seen during aging and in mice heterozygous for the null mutant of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (Gne+/-), an essential enzyme for sialic acid biosynthesis, contributes to retinal inflammation and degeneration. We found a reduction of polysialic acid and trisialic acid expression in several retinal layers in Gne+/- mice at 9 months of age, which was associated with a higher microglial expression of the lysosomal marker CD68. Furthermore, the total number of rod retinal bipolar cells was reduced in 12 months old Gne+/- mice, demonstrating loss of these retinal interneurons that are involved in connecting photoreceptors and ganglion cells. Whole-genome transcriptome analysis showed up-regulation of the complement, inflammation, and apoptosis pathways in the retinas of Gne+/- mice. Particularly, increased gene transcript levels of the complement factors C3 and C4 and the pro-inflammatory cytokine Il-1β were observed by semi-quantitative real-time polymerase chain reaction (sqRT-PCR) in 9 months old Gne+/- mice. The Iincreased expression of CD68, as well as the loss of rod bipolar cells, and increased gene transcription of the complement factor C4, were all prevented after crossing Gne+/- mice with complement factor C3-deficient animals. In conclusion, our data show that retinal hyposialylation in middle-aged Gne+/- mice, at 9 and 12 months of age, was associated with complement-related inflammation and lysosomal microglia response, as well as rod bipolar cells loss, which was absent in animals with a genetic deletion of complement factor C3.
2025-09-15 | GSE275072 | GEO
Project description:Mice heterozygous for the bifunctional enzyme glucosamine-2-epimerase/N-acetylmannosamine kinase (GNE+/-), which is essential for sialic acid biosynthesis, showed reduced gne transcription and sialylation in different brain regions. We found synapse loss in the hippocampus of GNE+/- mice at 6 months followed by a gradual loss of neurons in the hippocampus and substantia nigra at 12 months. Moreover, GNE+/- mice showed reduced arborization of microglia already at 6 months. A transcriptomic analysis revealed only minor inflammatory changes with slightly increased Interleukin 1β levels, indicating a homeostatic removal of synapses and neurons. Crossbreeding with complement component 3-deficient mice rescued the early onset loss of neurons and synapses in the GNE+/- mice. Thus, an intact sialic acid covered glycocalyx plays an essential role in maintaining brain homeostasis. Even a minor reduction in the sialic acid level leads to reduced microglial arborization and complement-mediated loss of neurons and synapses.
2019-10-07 | E-MTAB-7790 | biostudies-arrayexpress
Project description:Reduced sialylation triggers complement c3-mediated neuronal loss in aging mice
| PRJEB31769 | ENA
Project description:Chronic inflammatory bowel disease (IBD) causes disability, suffering and risk of colon cancer in over 30 million people globally. Here, we investigate 3 kindreds of IBD with mutations in the N-acetylgalactosamide alpha-2,6-sialyltransferase 1/ST6GALNAC1 (ST6) glycosyltransferase gene that is uniquely expressed in the goblet cells (GCs). These mutations cause defective sialic acid (SA) conjugation, elimination of the onco-antigen S-Tn (Sialyl-Tn), and altered glycosylation of the MUC2 protein, a key component of intestinal mucus. Decreased MUC2 sialylation increases susceptibility to bacterial proteolytic degradation and compromises the gastrointestinal (GI) mucus barrier. Mice harboring the patient ST6 mutations recapitulate human colitis and reveal that defective sialylation causes dysbiosis, butyrate overproduction, and impaired GI stem cell proliferation during injury. Thus, this new genetic disease illustrates how sialylation controls host-microbe homeostasis and reveals several new potential approaches to IBD treatment.
2022-03-16 | GSE183821 | GEO
Project description:Nutrient deprivation elicits a transcriptional and translational inflammatory response coupled to decreased protein synthesis
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Project description:Purpose: The complement system is closely linked to the pathogenesis of age-related macular degeneration (AMD). Several complement genes are expressed in retinal pigment epithelium (RPE), and complement proteins accumulate in drusen. Further, a common variant of complement factor H (CFH) confers increased risk of developing AMD. Because the mechanisms by which changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods: Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- C57BL/6J mice was analysed by microarrays. Expression of a wide range of complement genes was compared to expression in splenocytes and in liver tissue by qRT-PCR. Results: An age-associated increased expression of complement, particularly C1q, C3 and Factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Both hepatic and splenic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions: While the connection between CFH deficiency and failure to up-regulate CD59a remains unknown, these results suggest that expression of CD59 is tissue-specific and that neuroretinal regulation depends on CFH. This could contribute to the visual functional deficits and morphological changes in the Cfh-/- mouse retina that occur with age, and further suggests that deficient neuroretinal regulation of complement could represent an early event in AMD. Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- mice, 4 biological replicates in each group.
2012-10-02 | E-GEOD-38671 | biostudies-arrayexpress
Project description:Immunosuppressive tumor microenvironments (TME) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSC), precursors to cancer-associated fibroblasts (CAFs), dictate tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells that results in inhibition of effector functions. The role of sialylation in dictating MSC/CAF immunosuppression in the TME is unknown. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory PD-1, Siglec-7 and Siglec-9-expressing T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as evidenced by infiltration of CD25 and granzyme B-expressing T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.
2023-05-22 | GSE229054 | GEO
Project description:Purpose: The complement system is closely linked to the pathogenesis of age-related macular degeneration (AMD). Several complement genes are expressed in retinal pigment epithelium (RPE), and complement proteins accumulate in drusen. Further, a common variant of complement factor H (CFH) confers increased risk of developing AMD. Because the mechanisms by which changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods: Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- C57BL/6J mice was analysed by microarrays. Expression of a wide range of complement genes was compared to expression in splenocytes and in liver tissue by qRT-PCR. Results: An age-associated increased expression of complement, particularly C1q, C3 and Factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Both hepatic and splenic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions: While the connection between CFH deficiency and failure to up-regulate CD59a remains unknown, these results suggest that expression of CD59 is tissue-specific and that neuroretinal regulation depends on CFH. This could contribute to the visual functional deficits and morphological changes in the Cfh-/- mouse retina that occur with age, and further suggests that deficient neuroretinal regulation of complement could represent an early event in AMD.
2012-10-02 | GSE38671 | GEO
Project description:A better understanding of the proteomic profile after bipolar disorder (BD) and
schizophrenia (SCZ) treatment, through monitoring its progression, may assist
the development of novel therapeutic strategies with the ability to reduce or
control possible side effects. In this study, proteomics analysis employing liquid
chromatography coupled to mass spectrometry (LC-MS) and bioinformatic tools
were applied to identify differentially expressed proteins in serum of treated BD
and SCZ patients. In total, 10 BD patients, 10 SCZ patients, and 14 healthy
participants were included. From 25 serum proteins significantly altered (> 1.5-
fold change), 8 were down-regulated in the BD group, while 7 proteins were up-
regulated and 2 down-regulated in SCZ group when compared against healthy
controls. Bioinformatics analysis based on these 25 proteins validated two main
altered pathways previously described in the literature; furthermore, it revealed
that opposite expressions of the complement and coagulation cascades were
the most significant biological processes involved in these pathologies.
Associations of disease-proteins and pathways suggest therapeutic intervention
or prevention of comorbidities risks for BD and SCZ. Further validation and
investigation are required to define whether there is correlation between
complement and coagulation cascade expression for both diseases and
cardiovascular diseases.
2020-11-07 | MSV000086425 | MassIVE
Project description:The pathobiont S. aureus (SA) induces non-protective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which SA modify antibody activity is not clear. Herein, we show that IL-10 is the decisive factor that abrogates antibody protection. SA-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of sialyltransferase ST3gal4 and increases ST3gal4 expression by B cells, leading to hyper- a2,3 sialylation of antibodies and loss of protective activity. IL-10 enhances a2,3 sialylation on cell-wall associated IsdB, IsdA and MntC antibodies along with suppression of the respective SA vaccines. Consistent with mouse findings, human anti-SA antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects are hyper-sialylated, compared to anti-GAS and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10 leading to loss of staphylococcal vaccine efficacy.
2025-01-01 | GSE252557 | GEO