Conventional dendritic cells in atherosclerosis: from pathogenic players to targets for therapy?
29 November 2016
UAntwerp - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 Antwerpen (Wilrijk) (route: UAntwerpen, Campus Drie Eiken
5:00 PM - 7:00 PM
Phd defence Miche Rombouts - Department of Pharmaceutical Sciences
Atherosclerosis, the main underlying cause of cardiovascular disease, is associated with an enormous socio-economic burden. Its treatment is based on reducing risk factors. However, residual cardiovascular risk remains a major concern, which highlights room for additional improvement. Increasing evidence points to a role for immune processes as underlying disease mechanism in atherosclerosis. Dendritic cells (DCs) are antigen-presenting cells that can orchestrate both immunity and immunological tolerance. Given these functions, they are an unavoidable target in studying disease and in designing treatments. We aimed to unravel the contribution of conventional (c)DCs in atherosclerosis and to investigate if cDCs can be targeted for the treatment of atherosclerosis.
By conducting a longitudinal study in atherosclerosis-prone mice we demonstrated that, after 12 weeks on a Western-type diet, a clear turning point in immune cell dynamics occurs, in particular in the CD11b+ cDC subset. Strong correlations were found between circulating CD11b+ cDCs and natural killer (NK)T cells with plaque inflammation. Similarly, the number of circulating NKT cells in patients was predictive for the number of T and NKT cells in their plaques, independent of other risk factors. These results prompt the need for more in-depth research into the role of CD11b+ cDCs and NKT cells in atherosclerosis. Additionally, analysis of circulating leukocytes may provide a valuable tool to evaluate the inflammatory and immune status of the plaque.
Furthermore, to elucidate the role of cDCs in atherosclerosis we used the Zbtb46-DTR mouse model which allows selective depletion of cDCs by administration of DT. However, cDC depletion could not be sustained for a longer period of time, making this mouse model unsuitable to examine the effects of long-term depletion of cDCs.
Finally, we showed that the pathogenic immune response in atherosclerosis can be modulated via treatment with low-dose aspirin, and that tolerogenic DCs can be generated in vitro using IL-12p35 siRNA which ultimately can be used to restore the immunological balance in atherosclerosis. However, the complexity and heterogeneity of atherosclerosis may require integration of several tolerance induction mechanisms to fully control the disease. Future studies will need to establish the clinical benefits of using the combination of a lipid-lowering drug and an immunomodulatory therapy.