Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.

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

Abbreviations: AEC, 3-amino-9-ethyl carbazole; Arg1, Arginase 1; CCL2/MCP1, chemokine (C-C motif) ligand 2/Macrophage chemotactic protein-1; CCl 4 , carbon tetrachloride; CCR2, chemokine (C-C motif) receptor 2; DAPI, 4',6-diamidino-2-phenylindole; DMSO, Dimethyl sulfoxide; ECM, extracellular matrix; HRP, horseradish peroxidase; HSCs, hepatic stellate cells; IL-1β, Interleukin 1 beta; IL-6, Interleukin 6; MHC II, major histocompatibility complex class II; MRC1, mannose receptor 1; mRNA, messenger RNAs; NaCl, sodium chloride; NASH, non-alcoholic steatohepatitis; NOS2/iNOS, nitric oxide synthase 2; qRT-PCR, quantitative real-time polymerase chain reaction; SDS, sodium dodecyl sulfate; TGFβ, transforming growth factor beta; Tris-HCl, Tris(hydroxymethyl)aminomethane hydrochloride; YM1, Beta-N-acetyl hexosaminidase or Chi3l3, Chitinase-3-like protein 3; α-SMA, alpha smooth muscle actin. AbstractLiver diseases represent a major health problem worldwide, in particular, acute liver injury is associated with high mortality and morbidity. Inflammatory macrophages and hepatic stellate cells (HSCs) are known to be involved in the pathogenesis of acute liver injury. In this study, we have investigated the implication of STAT3 inhibition in acute liver injury/early fibrogenesis. In fibrotic human livers, we found STAT3 mRNA expression was significantly upregulated and correlated with collagen I expression. In vitro, STAT3 signaling pathway was found to be activated in TGFβ-activated HSCs and inflammatory macrophages. STAT3 inhibitor, WP1066 significantly inhibited TGFβ-induced collagen I, vimentin and α-SMA expression, and contractility in human HSCs. In LPS-and IFNγ-induced pro-inflammatory macrophages, WP1066 strongly attenuated nitric-oxide release and expression of major inflammatory markers such as TNF-α, iNOS, CCL2, IL-1β, IL-6, and CCR2. In vivo in CCl 4 -induced acute liver injury mouse model, WP1066 significantly reduced collagen expression, HSCs activation, and intrahepatic inflammation. Finally, in LPSinduced human hepatic 3D spheroid model, WP1066 inhibited LPS-induced fibrotic and inflammatory parameters. In conclusion, our results demonstrate that the therapeutic inhibition of STAT3 pathway using WP1066 targeting HSCs and inflammatory macrophages suggests a potential pharmacological approach for the treatment of acute liver injury. K E Y W O R D Sacute liver injury, hepatic stellate cells, inflammation, macrophages, STAT3 signaling pathway, WP1066 78 | ÖZTÜRK AKCORA eT Al.

Hepatic fibrosis, characterized by an excessive extracellular matrix (ECM) accumulation, leading to scar‐tissue formation is a growing health problem worldwide. Hepatocellular damage due to liver injury triggers inflammation and transdifferentiation of quiescent hepatic stellate cells (HSCs) into proliferative, contractile, and ECM‐producing myofibroblasts. Involvement of the Janus kinase (JAK)‐2 pathway in the pathogenesis of fibrosis has been reported earlier. However, in this study, we have investigated the effect of selective JAK2 antagonist TG101348 in fibroblasts and inflammatory macrophages and in vivo in an acute carbon tetrachloride–induced liver injury mouse model. In vitro, TG101348 significantly inhibited TGF‐β‐induced collagen I expression in murine 3T3 fibroblasts. In human HSCs (LX2 cells), TG101348 potently attenuated TGF‐β‐induced contractility and the protein and gene expression of major fibrotic parameters (collagen I, vimentin, and α‐smooth muscle actin). In LPS‐ and IFN‐γ‐stimulated inflammatory macrophages, TG101348 significantly reduced the NO release and strongly inhibited the expression of inflammatory markers (inducible nitric oxide synthase, C‐C motif chemokine ligand 2, IL‐1β, IL‐6, and C‐C chemokine receptor type 2). In vivo in an acute liver injury mouse model, TG101348 significantly attenuated collagen accumulation and HSC activation. Interestingly, TG101348 drastically inhibited macrophage infiltration and intrahepatic inflammation. Pharmacological inhibition of the JAK2 signaling pathway in activated HSCs and inflammatory macrophages using TG101348 suggests a potential therapeutic approach for the treatment of liver fibrosis.—Akcora, B. O., Dathathri, E., Ortiz‐Perez, A., Gabriël, A. V., Storm, G., Prakash, J., Bansal, R. TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo. FASEB J. 33, 9466–9475 (2019). http://www.fasebj.org

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