Abstract
The chemokine system of ligands and receptors is implicated in the progression of alcohol-associated hepatitis (AH). Finding upstream regulators could lead to novel therapies. This study involved coordinated expression of chemokines in livers of healthy controls (HC) and patients with AH in 2 distinct cohorts of patients with various chronic liver diseases. Studies in cultured hepatocytes and in tissue-specific KO were used for mechanistic insight into a potential upstream regulator of chemokine expression in AH. Selected C-X-C chemokine members of the IL-8 chemokine family and C-C chemokine CCL20 were highly associated with AH compared with HC but not in patients with liver diseases of other etiologies (nonalcoholic fatty liver disease [NAFLD] and hepatitis C virus [HCV]). Our previous studies implicate macrophage migration inhibitory factor (MIF) as a pleiotropic cytokine/chemokine with the potential to coordinately regulate chemokine expression in AH. LPS-stimulated expression of multiple chemokines in cultured hepatocytes was dependent on MIF. Gao-binge ethanol feeding to mice induced a similar coordinated chemokine expression in livers of WT mice; this was prevented in hepatocyte-specific Mif–KO (MifΔHep) mice. This study demonstrates that patients with AH exhibit a specific, coordinately expressed chemokine signature and that hepatocyte-derived MIF might drive this inflammatory response.
Highlights
Chemokines are small, leukocyte chemotactic proteins that are divided into families based upon conserved N-terminal cysteine (C) motifs
While changes in individual chemokine-receptor interactions have been studied in associated liver disease (ALD), our analysis identified a potentially novel coordinated chemokine expression signature in the liver that is distinctive in patients with associated hepatitis (AH) and likely dependent on migration inhibitory factor (MIF)-mediated signaling
Canonical functions of chemokines and MIF in ALD are associated with leukocyte infiltration into the liver, including monocytes, macrophages, and neutrophils [23,24,25]
Summary
Chemokines are small, leukocyte chemotactic proteins that are divided into families based upon conserved N-terminal cysteine (C) motifs. An interesting feature of chemokine biology is the inherent redundancy in the system — e.g., multiple ligands for a given receptor and ligands can bind multiple receptors [1, 2]. This biological redundancy of chemokine activity poses a significant challenge in targeting chemokine ligand–receptor interactions as potential therapeutics for the treatment of inflammatory diseases. Chemokines are associated with the progression of many diseases, including alcohol-associated liver disease (ALD) [3,4,5,6]. MIF is increased in liver and circulation of patients with AH and is associated with increased mortality in patients [12,13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
