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Ductular Reaction Cells Display an Inflammatory Profile and Recruit Neutrophils in Alcoholic Hepatitis
Author(s) -
AguilarBravo Beatriz,
RodrigoTorres Daniel,
Ariño Silvia,
Coll Mar,
Pose Elisa,
Blaya Delia,
Graupera Isabel,
Perea Luis,
Vallverdú Júlia,
RubioTomás Teresa,
Dubuquoy Laurent,
Armengol Carolina,
Lo Nigro Antonio,
Stärkel Peter,
Mathurin Philippe,
Bataller Ramon,
Caballería Joan,
José Lozano Juan,
Ginès Pere,
SanchoBru Pau
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30472
Subject(s) - proinflammatory cytokine , chemokine , cxcl2 , cxcl5 , transcriptome , alcoholic hepatitis , alcoholic liver disease , ccl20 , immunology , cxcl16 , organoid , laser capture microdissection , biology , cancer research , inflammation , cxcl10 , cirrhosis , medicine , gene expression , chemokine receptor , microbiology and biotechnology , gene , biochemistry
Chronic liver diseases are characterized by the expansion of ductular reaction (DR) cells and the expression of liver progenitor cell (LPC) markers. In alcoholic hepatitis (AH), the degree of DR expansion correlates with disease progression and short‐term survival. However, little is known about the biological properties of DR cells, their impact on the pathogenesis of human liver disease, and their contribution to tissue repair. In this study, we have evaluated the transcriptomic profile of DR cells by laser capture microdissection in patients with AH and assessed its association with disease progression. The transcriptome analysis of cytokeratin 7‐positive (KRT7 + ) DR cells uncovered intrinsic gene pathways expressed in DR and genes associated with alcoholic liver disease progression. Importantly, DR presented a proinflammatory profile with expression of neutrophil recruiting C‐X‐C motif chemokine ligand (CXC) and C‐C motif chemokine ligand chemokines. Moreover, LPC markers correlated with liver expression and circulating levels of inflammatory mediators such as CXCL5. Histologically, DR was associated with neutrophil infiltration at the periportal area. In order to model the DR and to assess its functional role, we generated LPC organoids derived from patients with cirrhosis. Liver organoids mimicked the transcriptomic and proinflammatory profile of DR cells. Conditioned medium from organoids induced neutrophil migration and enhanced cytokine expression in neutrophils. Likewise, neutrophils promoted the proinflammatory profile and the expression of chemokines of liver organoids. Conclusion : Transcriptomic and functional analysis of KRT7 + cells indicate that DR has a proinflammatory profile and promote neutrophil recruitment. These results indicate that DR may be involved in the liver inflammatory response in AH, and suggest that therapeutic strategies targeting DR cells may be useful to mitigate the inflammatory cell recruitment in AH.