Abstract Number: OC 22.4
Meeting: ISTH 2021 Congress
Background: We have previously shown that fibrin(ogen)-aMb2 interactions promote experimental colitis pathogenesis in mice, but the mechanistic details remain undefined.
Aims: Investigate the mechanisms coupling fibrin(ogen) to colitis pathogenesis.
Methods: We challenged control mice (FibWT) and gene-targeted mice carrying a mutant fibrinogen that lack the g chain binding motif for aMb2 (Fibg390-296A) with DSS. We performed flow cytometric, metabolomic and protein analyses of colons and stool microbiome after DSS exposure.
Results: Analyses of leukocyte subsets very early in the course of DSS (5 days of exposure) showed significant diminutions in natural killer cells, T cells, dendritic cells, macrophages and neutrophils in colons harvested from Fibg390-296A relative to control mice. We also observed upregulation of NK cell, dendritic cell and macrophage cytokine production in FibWT mice relative to mutant animals. Analyses of NMR-based metabolomics demonstrated significantly less uracil in stool from Fibg390-296A relative to FibWT mice following DSS exposure. Uracil is a key ligand for Duox2, a gut epithelial receptor that drives reactive oxygen species production by gut epithelial in response to dysbiosis. There was no difference in colonic Duox2 expression between genotypes at baseline, but Duox2 expression significantly increased in FibWT relative to Fibg390‑296A after just 5 days of DSS exposure. Consistent with this we also observed significantly higher levels of H2O2 in colons from DSS-challenged FibWT mice.
Conclusions: These data demonstrate that fibrin(ogen) in the colitis microenvironment promotes the infiltration and activation of multiple leukocyte subsets that drive colitis pathogenesis. These results also suggest that fibrin(ogen) promotes colitis-associated dysbiosis and Duox2 expression, leading to superoxide production. Increased local oxygen free radicals could contribute to epithelial mutagenesis, and represent an explanation for this increased adenoma formation previously seen in FibWT versus Fibg390-296A mice.
To cite this abstract in AMA style:Sharma BK, Kudira R, Rosenfeldt L, Gourley B, Milburn O, Haslam D, Watanabe-Chailland M, Romick-Rosendale L, Flick M, Palumbo J. Mechanisms Coupling Fibrinogen to Colitis Pathogenesis [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/mechanisms-coupling-fibrinogen-to-colitis-pathogenesis/. Accessed November 27, 2021.
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