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Type 1 conventional dendritic cells (cDC1) are a new target in non-alcoholic steatohepatitis (NASH)
Deczkowska A, David E, Ramadori P, et al. XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nat Med 2021; 27: 1043–54. doi: 10.1038/s41591-021-01344-3
The association between NASH and inflammation is well described, but the specific mechanisms by which inflammation promotes disease progression and how inflammation might be therapeutically targeted remain unclear. In this study, Deczkowska et al describe a novel role for a subpopulation of X-C motif chemokine receptor 1 positive cDC1 in NASH pathogenesis. Using a combination of single-cell RNA sequencing, immunohistochemistry and flow cytometry, they demonstrate expansion of liver cDC1 in mouse models of NASH. Interestingly, this was not observed in mouse models of obesity, suggesting that liver injury is required to increase cDC1 numbers. In parallel, they showed an increase in cDC1 in human NASH, which correlated positively with serum alanine aminotransferase and aspartate transaminase. Notably, cDC1 numbers were also increased in the blood of both patients and mice with NASH. Increased proliferation of bone marrow cDC1 precursors was observed in NASH mice, suggesting that systemic effects of liver injury may drive cDC1 expansion. The main function of cDC1 is to present antigens to cluster of differentiation 8 positive T cells and to promote cytotoxic responses. RNA sequencing of cDC1–T-cell pairs from liver draining lymph nodes showed increased inflammatory signalling in NASH mice, indicating that cDC1 may drive inflammation via enhanced T-cell activation. Functionally, blockade of liver cDC1 recruitment (using an XCL1 blocking antibody) or genetic depletion of cDC1 in a mouse NASH model reduced liver injury and inflammatory cell infiltration, highlighting the potential role of cDC1 in NASH pathogenesis. Blockade of cDC1 function may therefore represent a novel therapeutic strategy for patients with NASH.
Manipulation of interleukin-11 to alter the course of acute liver injury
Widjaja A, Dong J, Adami E, et al. Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic …
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.