Integrated cross-linking by TG2 and FXIII generates hepatoprotective fibrin(ogen) deposits in injured liver

The transglutaminase coagulation factor XIII (FXIII) is critical for the stability and function of intravascular fibrin clots. Prorepair extravascular fibrin(ogen) deposits are potentially subject to cross-linking by FXIII and other transglutaminases not typically resident in plasma. However, the impact of these alternative modifiers on fibrin(ogen) structure and function is not known. We tested the hypothesis that tissue transglutaminase (TG2) modifies FXIII-directed fibrin(ogen) cross-linking in vitro and within injured tissue. Global proteomic analysis after experimental acetaminophen (APAP)-induced acute liver injury revealed that intrahepatic fibrin(ogen) deposition was associated with hepatic TG2 levels that exceeded that of FXIII. Mass spectrometry-based cross-link mapping of in vitro fibrin matrices uncovered, to our knowledge, the first evidence of synergistic fibrin(ogen) α-α cross-linking catalyzed by both transglutaminases. Fibrin(ogen) cross-linking was increased in livers from patients with APAP-induced acute liver failure. APAP-challenged TG2^−/− mice displayed an altered pattern of FXIII-dependent fibrin(ogen)-γ and fibrin(ogen)-α chain cross-linking aligned with the impact of TG2 on fibrin cross-linking in vitro. This shift in fibrin(ogen) cross-linking exacerbated pathologies including hepatic necrosis and sinusoidal congestion. The results, to our knowledge, are the first to indicate that TG2 impacts FXIII-directed fibrin(ogen) cross-linking, both in vitro and in vivo. The results suggest that TG2 functions to dynamically alter the structure of extravascular fibrin(ogen) to mitigate liver damage, a novel mechanism likely applicable across types of tissue injury.