MAFLDCs · Elucidating Dendritic Cell Heterogeneity and Functions in Metabolic Associated Fatty Liver Disease
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-04-01 → 2023-03-31
- EU contribution
- €166,320
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
Elucidating Dendritic Cell Heterogeneity and Functions in Metabolic Associated Fatty Liver Disease
The key objective of this project was to identify the role of liver dendritic cells (DCs) in metabolic (dysfunction) associated liver disease (MAFLD). The rise in obesity and insulin resistance and therefore the accumulation of triglycerides and free fatty acids in the liver has resulted in a growing epidemic of NAFLD. This disease consists of a largely asymptomatic spectrum, whereby most patients have simple steatosis, a disease characterised by the retention of fat in the liver. The majority of patients do not progress through the disease spectrum, but for approximately twenty percent of patients, they will develop the more progressive form of disease, non-alcoholic steatohepatitis (NASH). This can lead to fibrosis, cirrhosis and in some instances, liver cancer (Hepatocellular Carcinoma; HCC). With the increasing prevalence of disease and the current lack of therapies, MAFLD is predicted to become the leading cause of liver transplantation in the Western world by 2030. However, despite its prevalence the mechanisms that drive disease progression in MAFLD remain incompletely understood. As key cytokine-producing antigen presenting cells, liver dendritic cells (DCs) unquestionably play important roles in the induction and regulation of hepatic inflammation, particularly in the context of T cell responses. However, due to difficulties in targeting them and potential heterogeneity within the total DC pool, studies extrapolating their functional characterisation, especially in the context of MAFLD, are limited. In addition, the existing research pertaining to their contribution in MAFLD progression is conflicting. Whilst some have observed a protective role of DCs in MAFLD, others have suggested they contribute to MAFLD development. The lack of effective therapies targeting MAFLD combined with the conflicting studies on DC role in MAFLD highlighted a significant gap in the literature that had the potential to provide information to guide therapeutic advances. The overall objectives of this project were to: characterise the heterogeneity of hepatic DCs in both steady state and during the development of NAFLD; identify the T cell responses induced by distinct cDC subsets; determine the consequences of manipulation cDC1 populations.
Data: CORDIS, © European Union
Project objective
The increasing clinical and societal burden of metabolic-associated fatty liver disease (MAFLD) coupled with the current lack of therapies highlights the need for a better understanding of the mechanisms driving this disease. In recent years, studies, including my own, have identified that MAFLD is accompanied by a change in the T cell subsets present in the liver and blood. However, the functions and causes of these altered populations remain largely unknown. Conventional dendritic cells (cDCs) function to sample antigens in the periphery and subsequently migrate to the lymph nodes (LNs) where they induce the proliferation and polarisation of naïve T cells, which then home back to the periphery to perform their functions. As such, by manipulating cDC function, we could potentially alter the T cells present in MAFLD and hence improve disease outcome. To date, studies of cDC function in MAFLD have been hampered by our limited understanding of cDC heterogeneity and the lack of specific tools with which to manipulate them in vivo. Building on the cDC expertise of the host lab, the single cell technologies established to dissect heterogeneity, and access to more specific models to target these cells, here, I aim to dissect cDC heterogeneity in the fatty liver. To this end, I will combine the mouse models of the host lab, with my expertise working with human material to identify the conserved features across humans and mice. As MAFLD is associated with an increase in CD8+ T cells, I hypothesize that by manipulating the main cDC subset associated with cross-presentation of antigen to naïve CD8+ T cells, namely the cDC1s, I can manipulate disease progression. Using the novel XCR1-CRE mouse model to specifically target cDC1s in vivo, I will investigate the in vivo functions of these cells in MAFLD and determine their potential for therapeutic intervention to improve patient outcome.
Original text from CORDIS.
Participants
- VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium
Links
Data: CORDIS, © European Union