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bioRxiv · 10.1101/2024.12.10.627861

Microthrombi-growth in ADAMTS13 deficiency exacerbated ulcerative colitis via mucosal and endothelial dysfunction

Tatsuta, K.·Honkura, N.·Morooka, N.·Sakata, M.·Kurachi, K.·Sugimoto, K.·Kokame, K.·Takeuchi, H.·Urano, T.·Suzuki, Y.
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Abstract

BackgroundUlcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation and ulceration, with systemic immune dysregulation exacerbating disease progression. While the accumulation of von Willebrand factor (VWF), normally digested by a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13) from ultra-large multimers to small molecules, has been implicated in UC pathogenesis, the association between aberrant microthrombus formation and colitis remains unclear. MethodsPlasma and inflamed colonic tissues from UC patients were analyzed. In the experimental colitis model, we employed an intravital imaging technique to reveal real-time structural dynamics of the mucus layer and the mucosal vasculature. Dextran sulfate sodium (DSS)-induced colitis in wild-type and ADAMTS13-deficient mice was evaluated for disease progression, mucus layer disruption, leukocyte recruitment, and thrombus formation in mucosal vessels using intravital multiphoton excitation microscopy within single-cell spatial resolution. ResultsUC patients exhibited significantly reduced plasma ADAMTS13 activity correlating with disease severity and excessive VWF deposition in inflamed colonic tissues. In DSS-induced colitis mice, ADAMTS13 deficiency showed heightened disease activity and increased mucosal erosion in histochemical analysis compared to wild-type mice. A novel methodology established in this study using intravital microscopy successfully appraised colonic mucus barrier integrity by visualizing fluorescent dextran penetration from the colonic lumen to the crypts. ADAMTS13 deficiency accelerated mucus layer disruption, leukocyte adhesion, and microthrombi formation, particularly close to crypt epithelium regions. Vessel-specific analyses demonstrated that obstructive microthrombi were most prominent in the mucosal layer, contributing to local ischemia and mucosal erosion. Therapeutical usage of recombinant human ADAMTS13 alleviated microthrombus formation, improved mucosal integrity, and mitigated colitis severity in wild-type and ADAMTS13-deficient mice. ConclusionsObstructive thrombi formed in mucosal vessels due to impaired ADAMTS13 activity appeared essential in the disease progression of UC. Advanced intravital imaging provided novel insights into single-cell resolution UC pathogenesis.

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Tatsuta, K., Honkura, N., Morooka, N., Sakata, M., Kurachi, K., Sugimoto, K., Kokame, K., Takeuchi, H., Urano, T., Suzuki, Y.. 2024-12-16. Microthrombi-growth in ADAMTS13 deficiency exacerbated ulcerative colitis via mucosal and endothelial dysfunction. https://doi.org/10.1101/2024.12.10.627861

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