Inflammatory type 2 conventional dendritic cells contribute to murine and human cholangitis.

Authors:

Anna-Lena Müller, Christian Casar, Max Preti, Daria Krzikalla, Cornelia Gottwick, Pia Averhoff, Philip Rosenstiel, Mathias Gelderblom, Marcus Altfeld, Ansgar W Lohse, Silja Steinmann, Marcial Sebode, Jenny Krause, Dorothee Schwinge, Christoph Schramm, Antonella Carambia, Johannes Herkel

Year of publication:

2022

Volume:

77

Issue:

6

ISSN:

0168-8278

Journal (long):

Journal of hepatology : the journal of the European Association for the Study of the Liver

Journal (short):

J HEPATOL

Impact factor:

30.083

Abstract:

Background & aims

Primary sclerosing cholangitis (PSC) is a progressive cholangiopathy characterised by fibrotic stricturing and inflammation of bile ducts, which seems to be driven by a maladaptive immune response to bile duct injury. The histological finding of dendritic cell expansion in portal fields of patients with PSC prompted us to investigate the role of dendritic cells in orchestrating the immune response to bile duct injury.

Methods

Dendritic cell numbers and subtypes were determined in different mouse models of cholangitis by flow cytometry based on lineage-imprinted markers. Findings were confirmed by immunofluorescence microscopy of murine livers, and liver samples from patients with PSC were compared to control samples from bariatric surgery patients. Using genetic tools, selected dendritic cell subsets were depleted in murine cholangitis. The dendritic cell response to bile duct injury was determined by single-cell transcriptomics.

Results

Cholangitis mouse models were characterised by selective intrahepatic expansion of type 2 conventional dendritic cells, whereas plasmacytoid and type 1 conventional dendritic cells were not expanded. Expansion of type 2 conventional dendritic cells in human PSC lesions was confirmed by histology. Depletion studies revealed a proinflammatory role of type 2 conventional dendritic cells. Single-cell transcriptomics confirmed inflammatory maturation of the intrahepatic type 2 conventional dendritic cells and identified dendritic cell-derived inflammatory mediators.

Conclusions

Cholangitis is characterised by intrahepatic expansion and inflammatory maturation of type 2 conventional dendritic cells in response to biliary injury. Therefore, type 2 conventional dendritic cells and their inflammatory mediators might be potential therapeutic targets for the treatment of PSC.

Lay summary

Primary sclerosing cholangitis (PSC) is an inflammatory liver disease of the bile ducts for which there is no effective treatment. Herein, we show that the inflammatory immune response to bile duct injury is organised by a specific subtype of immune cell called conventional type 2 dendritic cells. Our findings suggest that this cell subtype and the inflammatory molecules it produces are potential therapeutic targets for PSC.

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