From NAFLD to NASH to fibrosis to HCC: Role of dendritic cell populations in the liver

D endritic cells (DCs) are particular hematopoietic cells that link the innate and adaptive part of immune responses. DCs, regularly found in lymphoid and nonlymphoid tissues, are specialized cells for presenting antigens in conjunction with major histocompatibility complex (MHC) class II molecules to T cells for initiating antigen-specific immune responses. Although DCs share certain characteristics, such as intracellular processing of phagocytized peptides and proteins for antigen presentation, migratory properties (toward the draining lymph node), and cytokine production, several functionally distinct DC subsets have been unraveled in mice and humans. However, most of these DC functions have been uncovered in infectious or autoimmune disease models in typical lymphoid organs, such as spleen or lymph nodes, and relatively little is known at present on the possible roles of DC populations in the liver. Moreover, given that many conditions of liver inflammation, such as nonalcoholic steatohepatitis (NASH), are classically considered noninfectious inflammatory reactions and are certainly not directed against a single antigen, unlike immune responses against viral proteins in viral hepatitis, the relevance of DCs for regulating sterile liver inflammation and fibrosis is even less clear. Nevertheless, independent studies had reported on the accumulation of myeloid cells with DC characteristics in experimental models of toxic and cholestatic liver diseases. In this issue of Hepatology, Henning et al. explored the potential role of DCs in regulating hepatic inflammation and fibrogenesis in NASH (Fig. 1). Upon induction of experimental steatohepatitis by feeding a methionine-choline deficient (MCD) diet over 6 weeks, the number of DCs, as defined by positive staining for the leukocyte marker, CD45, the mouse DC marker, CD11c, and MHC class II molecules, markedly increased in injured livers. In comparison to normal livers, NASH-associated DCs showed a more mature phenotype with respect to expression of costimulatory molecules, produced increased levels of cytokines, and displayed an enhanced capacity to activate antigen-specific CD4 T cells, but not CD8 T cells, when isolated from steatotic murine livers. From these data, one could have speculated that these DCs promote inflammatory reactions in NASH. To test the functional role of these cells in vivo, the researchers used a mouse model to deplete these cells continuously during NASH progression by administration of diphtheria toxin (DT) to bone marrow chimeric mice, in which all hematopoietic cells carried the diphtheria toxin receptor (DTR) on CD11c-expressing cells. Surprisingly, depletion of CD11c-expressing cells augmented intrahepatic inflammation, especially the activation of neutrophils, Kupffer cells, and inflammatory monocytes in injured livers, increased the number of apoptotic cells, and accelerated hepatic fibrosis. The researchers provide some indirect data supporting that DCs may limit inflammation in NASH liver by clearing necrotic cellular debris and apoptotic bodies, which would fit well with the observed increased number and activation of innate immunity in DC-depleted mice (Fig. 1). Furthermore, when DCs were abrogated during recovery from MCD diet, DC depletion delayed the resolution of experimental NASH, which is well in agreement with an earlier study demonstrating that DCs facilitate fibrosis regression in a model of sterile toxic liver injury by carbon tetrachloride. The elegant study by Henning et al. strongly indicates beneficial functions of hepatic DCs in limiting fibroinflammatory reactions in the steatotic environment (Fig. 1), which might thus represent an attractive target for future therapeutic strategies. Nevertheless, before developing DC-based immunomodulatory Abbreviations: DC, dendritic cell; DT, diphtheria toxin; DTR, diphtheria toxin receptor; HCC, hepatocellular carcinoma; MCD, methionine-choline deficient; MDSCs, myeloid-derived suppressor cells; MHC, major histocompatibility complex; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. Address reprint requests to: Frank Tacke, M.D., Ph.D., Department of Medicine III, University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail: frank.tacke@gmx.net; fax: 149-241-8082455. This work was supported by the German Research Foundation (SFB/TRR57; Ta434/2-1). Copyright VC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26405 Potential conflict of interest: Nothing to report.