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

被引：13

作者：

Muller, Anna-Lena ^{[1
]}

Casar, Christian ^{[1
,2
]}

Preti, Max ^{[1
]}

Krzikalla, Daria ^{[1
]}

Gottwick, Cornelia ^{[1
]}

Averhoff, Pia ^{[1
]}

Rosenstiel, Philip ^{[3
]}

Gelderblom, Mathias ^{[4
]}

Altfeld, Marcus ^{[5
,6
]}

Lohse, Ansgar W. ^{[1
,7
]}

Steinmann, Silja ^{[1
]}

Sebode, Marcial ^{[1
]}

Krause, Jenny ^{[1
]}

Schwinge, Dorothee ^{[1
,7
]}

Schramm, Christoph ^{[1
,7
,8
]}

Carambia, Antonella ^{[1
,7
]}

Herkel, Johannes ^{[1
,7
]}

机构：

[1] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Martinistr 52, D-20246 Hamburg, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Bioinformat Core Facil, Hamburg, Germany

[3] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[4] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany

[5] Univ Med Ctr Hamburg Eppendorf, Dept Immunol, Hamburg, Germany

[6] Heinrich Pette Inst, Leibniz Inst Expt Virol, Dept Virus Immunol, Hamburg, Germany

[7] Univ Med Ctr Hamburg Eppendorf, Hamburg Ctr Translat Immunol, Hamburg, Germany

[8] Univ Med Ctr Hamburg Eppendorf, Martin Zeitz Ctr Rare Dis, D-20246 Hamburg, Germany

来源：

JOURNAL OF HEPATOLOGY | 2022年 / 77卷 / 06期

关键词：

Cholangitis; bile duct; dendritic cells; Th17; inflammation; SCLEROSING CHOLANGITIS; OSTEOPONTIN EXPRESSION; NLRP3; INFLAMMASOME; T-CELLS; ACTIVATION; REVEALS; DIFFERENTIATION; RECRUITMENT; IL-1-BETA; MONOCYTES;

D O I：

10.1016/j.jhep.2022.06.025

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：1532 / 1544

页数：14

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