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Cell cyclin kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1

ABSTRACT: Sle2c1 is an NZM2410-derived lupus susceptibility locus that induces an expansion of the B1a cell compartment. B1a cells have a repertoire enriched for autoreactivity, and an expansion of this B cell subset occurs in several mouse models of lupus. Here we showed that expression of Sle2c1 enhances NZB cellular phenotypes that have been associated with autoimmune pathogenesis. A combination of genetic mapping and candidate gene analysis presents Cdkn2c, a gene encoding for cyclin kinase inhibitor p18INK4c (p18), as the top candidate gene for inducing the Slec2c1 associated expansion of B1a cells. A novel SNP in the Cdkn2c promoter is associated with a significantly reduced Cdkn2c expression in the splenic B cells and B1a cells from Sle2c1-carrying mice, which leads to defective G1 cell cycle arrest in splenic B cells and increased proliferation of Pc B1a cells. As cell cycle is differentially regulated in B1a and B2 cells, these results suggest that Cdkn2c play a critical role in B1a cell self renewal, and that its impaired expression leads to an accumulation of these cells with high autoreactive potential.

ORGANISM(S): Mus musculus

PROVIDER: GSE23114 | GEO | 2010/07/24

SECONDARY ACCESSION(S): PRJNA131501

REPOSITORIES: GEO

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Project description:Abstract Introduction Several environmental stimuli may influence lupus, especially viral infection. We utilize an imiquimod-induced lupus mouse model focusing on TLR7 pathway and use proteomics analysis to figure out the specific pathway related to viral infection and its related protein expressions in splenic B cells, hoping to get an insight on B cell responses to viral infection in lupus model. Material and methods. FVB/N wild type mouse was used treated with imiquimod for 8 weeks to induce lupus symptoms and signs, and splenocytes were retrieved, and B cells were selected and conducted proteomic analysis. The B cells were co-cultured with CD40L+ feeder cells for another one week before Western blot analysis. Panther pathway analysis was used to disclose the pathways activated and protein-protein interactome analyzed by STRING database in this lupus murine model. Results. The lupus model is well established and well demonstrated with serology evidence and pathology proof of lupus-mimic organ damage. Proteomics data of splenic B cells revealed the most important pathways activated (fold enrichment >100) were positive regulation of MDA-5 signaling pathway, negative regulation of IP-10 production, negative regulation of chemokine (C-X-C motif) ligand 2 production and positive regulation of RIG-I signaling pathway. A unique protein-protein interactome containing 10 genes was discovered, within which ISG15, IFIH1, IFIT1, DDX60, and DHX58 have been demonstrated to be downstream effectors of MDA5 signaling. Finally, B cells intracellular cytosolic proteins were determined with Western blot experiment and the MDA5-related pathway activation is still evident. Conclusion. In this experiment, we confirmed that the B cells in lupus murine model focusing on TLR7 pathway were activated through MDA5 signaling pathway, an important RNA sensor implicated in the detection of viral infections and autoimmune. The MDA5 agonists/antagonist RNAs and detailed molecular interactions inside B cells are worthy further investigation for lupus therapy.

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Cell cyclin kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1

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