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Fibrin is a critical regulator of neutrophil effector function at mucosal barrier sites

ABSTRACT: Plasminogen (Plg), the zymogen precursor of the serine protease plasmin, is synthesized by the liver and is present in high concentration in the circulation and in interstitial fluids to provide focal proteolysis, after being converted to plasmin by urokinase or tissue plasminogen activator. Homozygous or compound heterozygous mutations in the human Plg gene (PLG) typically lead to severe mucosal disease involvement suggesting, a critical role for this gene/pathway in mucosal immunity. Indeed, such patients present with deposition of fibrin at various mucosal sites leading to ocular disease (conjunctivitis), oral mucosal disease (ligneous periodontitis), lung, vaginal and gastrointestinal tract involvement. In the oral mucosa, local deposition of fibrin is hypothesized to lead to severe soft tissue and bone destruction around teeth and often loss of the entire dentition in adolescence. Mucosal inflammation in areas surrounding the dentition and destruction of underlying bone are also the hallmarks of the common human oral mucosal disease, periodontitis. Plg-deficient mice phenocopy the human disease and we aim to use this animal model to understand the mechanism underlying fibrin-mediated periodontal immunopathology in vivo. Herein, we analyse the transcriptome of gingival tissues extracted from Plg-deficient mice in comparison to their wild-type littermates at 12 weeks of age.

ORGANISM(S): Mus musculus

PROVIDER: GSE178616 | GEO | 2022/06/02

REPOSITORIES: GEO

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Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.

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Fibrin is a critical regulator of neutrophil effector function at mucosal barrier sites

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