Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis

Christina Andersson,Joseph S Palumbo,Peter H Kvist,Brian Turpin,Thomas L Holm,Hermann Pelzer,Whitney Miller,David Wu,Luise K Gram,Simon Hogan,Richard Baylis,Kathryn Mcelhinney,Brian Lauritzen,Jörn Karhausen

doi:10.1371/journal.pone.0128113

Christina Andersson, Joseph S Palumbo + Show 12 more

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https://doi.org/10.1371/journal.pone.0128113

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Abstract

The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes. Here, gene-targeted mice lacking the FXIII catalytic A subunit were employed to directly test the hypothesis that FXIII limits colonic pathologies associated with experimental colitis. Wildtype (WT) and FXIII-/- mice were found to be comparable in their initial development of mucosal damage following exposure to dextran sulfate sodium (DSS) challenge. However, unlike FXIII-sufficient mice, FXIII-deficient cohorts failed to efficiently resolve colonic inflammatory pathologies and mucosal damage following withdrawal of DSS. Consistent with prior evidence of ongoing coagulation factor activation and consumption in individuals with active colitis, plasma FXIII levels were markedly decreased in colitis-challenged WT mice. Treatment of colitis-challenged mice with recombinant human FXIII-A zymogen significantly mitigated weight loss, intestinal bleeding, and diarrhea, regardless of whether cohorts were FXIII-sufficient or were genetically devoid of FXIII. Similarly, both qualitative and quantitative microscopic analyses of colonic tissues revealed that exogenous FXIII improved the resolution of multiple colitis disease parameters in both FXIII-/- and WT mice. The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis. These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

Highlights

The plasma transglutaminase factor XIII (FXIII) is most well recognized as the enzyme that stabilizes fibrin clots by covalently crosslinking specific glutamyl- and lysyl- side chains on assembled fibrin monomers [1, 2]
In order to directly determine if FXIII plays a role in the development and resolution of experimental colitis in vivo, FXIII-A deficient (FXIII−/−) and WT littermate control mice were enrolled in colitis studies initiated by dextran sulfate sodium (DSS)-induced mucosal damage
WT mice quickly showed a cessation of intestinal bleeding, diarrhea and weight loss when transitioned to normal water, resulting in both a significantly lower and an declining Disease Activity Index (DAI) score following DSS withdrawal compared to FXIII−/− mice

Summary

Introduction

The plasma transglutaminase factor XIII (FXIII) is most well recognized as the enzyme that stabilizes fibrin clots by covalently crosslinking specific glutamyl- and lysyl- side chains on assembled fibrin monomers [1, 2]. Prolonged wound healing has been reported in humans with severe FXIII deficiency [4,5,6,7]. Consisted with these reports, animal studies showed that FXIII-deficient mice exhibit delayed cutaneous wound closure relative to FXIII-sufficient mice [8]. A role for FXIII in wound healing is suggested by studies showing that FXIII-deficient mice exhibit a delay in hepatocyte regeneration following carbon tetrachloride induced liver injury [9]. A role for FXIII in the repair of damaged myocardium is suggested by studies showing an increased incidence of cardiac rupture in FXIIIdeficient mice relative to control animals following experimental mycoardial infarction [11]

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