Fibrin deposition following bile duct injury limits fibrosis through an α _Mβ ₂-dependent mechanism

Abstract

Publisher's Note: There is an [Related article:]Inside Blood Commentary on this article in this issue.

Key Points

• Fibrin engagement of leukocyte integrin-α _Mβ ₂ restricts bile duct hyperplasia and inhibits periductal fibrosis.

• Periductal fibrosis following bile duct injury is inhibited by leukadherin-1, an allosteric activator of integrin-α _Mβ ₂ fibrin binding.

Abstract

Coagulation cascade activation and fibrin deposits have been implicated or observed in diverse forms of liver damage. Given that fibrin amplifies pathological inflammation in several diseases through the integrin receptor α _Mβ ₂, we tested the hypothesis that disruption of the fibrin(ogen)-α _Mβ ₂ interaction in Fibγ ^390-396A mice would reduce hepatic inflammation and fibrosis in an experimental setting of chemical liver injury. Contrary to our hypothesis, α-naphthylisothiocyanate (ANIT)–induced liver fibrosis increased in Fibγ ^390-396A mice, whereas inflammatory cytokine expression and hepatic necrosis were similar to ANIT-challenged wild-type (WT) mice. Increased fibrosis in Fibγ ^390-396A mice appeared to be independent of coagulation factor 13 (FXIII) transglutaminase, as ANIT challenge in FXIII-deficient mice resulted in a distinct pathological phenotype characterized by increased hepatic necrosis. Rather, bile duct proliferation underpinned the increased fibrosis in ANIT-exposed Fibγ ^390-396A mice. The mechanism of fibrin-mediated fibrosis was linked to interferon (IFN)γ induction of inducible nitric oxide synthase (iNOS), a gene linked to bile duct hyperplasia and liver fibrosis. Expression of iNOS messenger RNA was significantly increased in livers of ANIT-exposed Fibγ ^390-396A mice. Fibrin(ogen)-α _Mβ ₂ interaction inhibited iNOS induction in macrophages stimulated with IFNγ in vitro and ANIT-challenged IFNγ-deficient mice had reduced iNOS induction, bile duct hyperplasia, and liver fibrosis. Further, ANIT-induced iNOS expression, liver fibrosis, and bile duct hyperplasia were significantly reduced in WT mice administered leukadherin-1, a small molecule that allosterically enhances α _Mβ ₂-dependent cell adhesion to fibrin. These studies characterize a novel mechanism whereby the fibrin(ogen)–integrin-α _Mβ ₂ interaction reduces biliary fibrosis and suggests a novel putative therapeutic target for this difficult-to-treat fibrotic disease.