Inflammatory type 2 conventional dendritic cells contribute to cholangitis in mice

Background The pathogenesis of primary sclerosing cholangitis (PSC) is not well understood. It is likely that dendritic cells (DCs) contribute to PSC pathogenesis. Because they are sentinel cells that reside close to bile ducts within the portal fields, they can readily recruit other inflammatory cells upon activation, and they are potent antigen-presenting cells that can effectively activate the adaptive immune system. However, the actual role of DCs in PSC is not clear.

Methods To characterise the contribution of DCs to PSC pathogenesis, we used three different mouse models that represent various aspects of PSC. 1) Acute 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangitis; 2) Mdr2 knock-out mice that spontaneously develop a bile toxicity-driven cholangiopathy; 3) K14-OVAp mice expressing an ovalbumin peptide in cholangiocytes that developed T cell-driven cholangiopathy following adoptive transfer of cognate OT1 T cells recognizing the ovalbumin peptide. Liver dendritic cells were characterised by applying a flow cytometry gating strategy that was previously developed by unsupervised analysis of flow cytometry data. Moreover, in the DDC model, DCs isolated from livers were subjected to single-cell transcriptomics using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq).

Results Cholangitis in all three mouse models was associated with strongly decreased relative numbers of plasmacytoid dendritic cells (pDCs) and conventional type 1 DCs (cDC1). In contrast, all three cholangitis models were characterised by a significant expansion of hepatic CD11c+ MHC II+ IRF8- CD172+ conventional type 2 DCs (cDC2), which compensated the decrease of the other DC populations, even leading to an overall increase in liver DCs in the DDC model and Mdr2 knock-out mice. Single-cell transcriptomic data confirmed these findings and revealed that the remaining pDCs and cDC1 cells were transcriptionally rather unresponsive to cholangitis induction. In contrast, the expanded cDC2 population was strongly responsive to cholangitis induction and seemed to acquire a mature state with inflammatory activity.

Conclusions Cholangitis in different mouse models was associated with expansion of conventional type 2 DCs showing inflammatory activity. Thus, cDC2 cells and their inflammatory mediators might be a target for treatment of PSC.

Publikationsverlauf

Artikel online veröffentlicht:
04. Januar 2021