Mast cells produce factor XIIIA and mast cell chymase reduces factor XIIIa activity during sepsis through proteolytic degradation (HYP5P.318)

Abstract

Abstract Previously, we reported that mast cell (MC) chymase, and its mouse homologue, mast cell protease 4 (MCPT4), protect from septic morbidity and mortality by limiting inflammation via TNF degradation. Here, we identified another potential MCPT4 substrate; factor XIIIa (FXIIIa; the essential fibrin-crosslinking/clot stabilizing FXIII catalytic subunit). We found that extracellular FXIIIA (the pro-form of FXIIIa) protein levels were significantly increased in IgE-stimulated MCPT4-/- peritoneal MC (PMC) supernatants compared with WT PMCs (FXIIIA mRNA levels were unchanged). These data suggest that MCs both secrete FXIIIA and are capable of degrading it via MCPT4. Based on these results, and on published data demonstrating that FXIIIa activity correlated with sepsis severity, we hypothesize that chymase/MCPT4 mediated cleavage of FXIIIa participates in the previously-noted protective effect of chymase during sepsis. First, we verified that chymase is capable of degrading FXIIIA and reducing FXIIIa activity in-vitro and in-vivo. Additionally, we identified 6 chymase-driven primary cleavage sites in human FXIIIA. Finally, we observed that following experimentally-induced sepsis, plasma and peritoneal FXIIIA levels as well as plasma FXIIIa activity were significantly diminished in WT compared with MCPT4-/- mice. In conclusion, these data demonstrate that MCs produce FXIIIA and that MCPT4 reduces FXIIIa activity during experimental sepsis.