High Mobility Group Box 1 Release by Cholangiocytes Governs Biliary Atresia Pathogenesis and Correlates With Increases in Afflicted Infants

Abstract

These results suggest that HMGB1 plays a role in virus induced BA pathogenesis and could be a target for therapeutic interventions in a subset of patients with BA and high HMGB1. (Hepatology 2021;74:864-878). B iliary atresia (BA) is a disease of infancy in which a devastating fibroinflammatory cholangiopathy occurs, leading to obstructive jaundice. BA leads to end-stage liver disease (ESLD). (1)(2)(3)(4) In the United States, the incidence of BA is 1 in 15,000 births, (5) and it is the most common indication for pediatric liver transplantation. (6,7) In an effort to restore bile flow, a Kasai hepatoportoenterostomy (HPE) is typically performed soon after diagnosis. (8) However, even if an HPE is performed and cholestasis resolves, bile duct proliferation and fibrosis may progress, (7) resulting in the development of portal hypertension and the complications of ESLD. (9) It is estimated that 60% of the patients who overcome perinatal cholestasis will still need a liver transplantation before the age

The mechanism of HMGB1 secretion and release

“…They conduct extracellular signals through a tertiary kinase cascade, specifically, extracellular signal → MAPK kinase (MKKK) → MAPK kinase (MKK) → MAPK 127 . MAPK family members divergently contribute to HMGB1 release in different inflammatory and injury models 128 – 131 . For example, the expression and release of HMGB1 is mediated through the p38 MAPK signaling pathway induced by rhesus rotavirus, while inhibition of p38 prevents HMGB1 release in cholangiocytes 131 .…”

“…MAPK family members divergently contribute to HMGB1 release in different inflammatory and injury models 128 – 131 . For example, the expression and release of HMGB1 is mediated through the p38 MAPK signaling pathway induced by rhesus rotavirus, while inhibition of p38 prevents HMGB1 release in cholangiocytes 131 . MAPK-mediated HMGB1 secretion is also implicated in endothelial inflammation, thus providing a potential therapeutic strategy for vascular diseases 132 .…”

Biliary Atresia – emerging diagnostic and therapy opportunities

“…Inflammation is intimately associated with BA. In a recent report, RRV infection in mice was shown to cause increased expression and release of the protein HMGB1, which has been implicated in mediating inflammation [71] . HMGB1 induction was mediated via the p38 MAPK signalling pathway, which offers potential therapeutic opportunities.…”

Letter to the Editor: High Mobility Group Box Protein 1 Release Is an Identified Driver of Inflammation in the Pathogenesis of Biliary Atresia

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<FNTX>Abbreviations: BA, biliary atresia; HMGB1, high mobility group box protein 1; ICO, human cholangiocyte organoid<FNTX> With great interest, we read the study by Mohanty S et al (1) demonstrating that rotavirus-infected cholangiocytes actively release high mobility group box protein 1 (HMGB1), contributing to the pathogenesis of biliary atresia (BA). The activation of HMGB1 secretion involves viral induction of reactive oxygen species and is mediated by the p38/STAT1 axis.

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“…Immunosuppression agents, such as corticosteroids, have been applied to confine inflammation during the Kasai procedure but showed contradictory results. (1) Mohanty et al (1) now identified serum HMGB1 as a non-invasive biomarker, possibly reflecting "the right window" for anti-inflammatory therapy. This novel insight may also help to stratify BA patients together with histological scoring approaches and molecular signatures, such as inflammatory, virus, fibrotic, and cell death-related markers, to improve the therapeutic effect.…”