Mitigation of portal fibrosis and cholestatic liver disease in ANKS6 ‐deficient livers by macrophage depletion

Abstract

Congenital hepatic fibrosis (CHF) is a developmental liver disease that is caused by mutations in genes that encode ciliary proteins and is characterized by bile duct dysplasia and portal fibrosis. Recent work has demonstrated that mutations in ANKS6 can cause CHF due to its role in bile duct development. Here, we report a novel ANKS6 mutation, which was identified in an infant presenting with neonatal jaundice due to underlying biliary abnormalities and liver fibrosis. Molecular analysis revealed that ANKS6 liver pathology is associated with the infiltration of inflammatory macrophages to the periportal fibrotic tissue and ductal epithelium. To further investigate the role of macrophages in CHF pathophysiology, we generated a novel liver‐specific Anks6 knockout mouse model. The mutant mice develop biliary abnormalities and rapidly progressing periportal fibrosis reminiscent of human CHF. The development of portal fibrosis in Anks6 KO mice coincided with the accumulation of inflammatory monocytes and macrophages in the mutant liver. Gene expression and flow cytometric analysis demonstrated the preponderance of M1‐ over M2‐like macrophages at the onset of fibrosis. A critical role for macrophages in promoting peribiliary fibrosis was demonstrated by depleting the macrophages with clodronate liposomes which effectively reduced inflammatory gene expression and fibrosis, and ameliorated tissue histology and biliary function in Anks6 KO livers. Together, this study demonstrates that macrophages play an important role in the initiation of liver fibrosis in ANKS6‐deficient livers and their therapeutic elimination may provide an avenue to mitigate CHF in patients.

The Han:SPRD Rat: A Preclinical Model of Polycystic Kidney Disease

“…Histological analyses show mild periportal fibrosis, inflammatory infiltrations (primarily in the connective tissue of the portal locations [35]), a sharp reduction in the thickness of the periportal mesenchyme, and a complete absence of peribiliary fibroblasts, indicating that the abnormalities in portal morphogenesis may be caused by impaired crosstalk between the biliary epithelium and the portal mesenchyme [73]. These findings in humans and in an orthologous anks6 knockout mouse model offer compelling evidence in support of the hypothesis that CHF is caused by the activation of pro-inflammatory signaling in the periportal space by activated bile duct epithelial cells [75]. Moreover, cysts have also been described in humans with ADPKD in other organs including the pancreas, lungs, spleen, ovaries, testes, epididymis, thyroid, uterus, broad ligament, and bladder.…”

Biallelic ANKS6 null variants cause notable extrarenal phenotypes in a nephronophthisis patient and lead to hepatobiliary abnormalities by YAP1 deficiency

“…Thus, it seems that ANKS6 possesses relatively redundant functions in the development and maintenance of the hepatobiliary system: even if only a little function is reserved, it can meet the requirement for normal development; only complete loss of function will lead to hepatobiliary manifestations. Consistently, two ANKS6 knockout mouse models have been reported with biliary abnormalities and liver fibrosis 12,27 . However, the exact molecular pathogenesis remains to be elucidated.…”

“…with biliary abnormalities and liver fibrosis. 12,27 However, the exact molecular pathogenesis remains to be elucidated.…”

Targeting osteopontin to treat primary sclerosing cholangitis

“…Moreover, secreted CD206 levels can predict transplant-free survival in PSC patients [21–23]. Macrophages are also enriched in livers of various murine models of cholestatic liver injury and periportal fibrosis, including Mdr2 −/− knockout mice and the common bile duct ligation (CBDL) model [23–25].…”