Direct immunomodulatory effects of DSPC:DSPG:CHOL liposomes on murine dendritic cells

Abstract

Autoimmune diseases affect around 7-9% of the population world-wide and there is no cure for these diseases. Delivering disease-causing self-antigens in a tolerance-enhancing manner can halt the inappropriate immune response that characterizes autoimmunity. This can be achieved by delivery systems such as liposomes which are readily taken up by antigen presenting cells such as macrophages and dendritic cells. Liposomes composed of phosphatidylserine are known to induce antigen-specific tolerance since phosphatidylserine, a natural tolerance-enhancer, is expressed on the surface of apoptotic cells. We have previously demonstrated that antigen encapsulated in liposomes composed of a different phospholipid, phosphatidylglycerol also induces antigen-specific tolerance. However, the direct immunomodulatory effects of phosphatidylglycerol-containing liposomes on antigen presenting cells have not been studied in detail. We examined several markers for maturation and activation, and measured cytokine production by murine bone marrow-derived dendritic cells stimulated by liposomes or apoptotic cells. Both liposomes and apoptotic cells were efficiently phagocytosed in a process that was blocked by cytochalasin D. RAC1 was highly upregulated in the dendritic cells after uptake of liposomes or apoptotic cells, which coincided with a decrease in LPS-induced COX2, NFKB, and MTORC1 expression. Only apoptotic cells increased the expression of IDO1 and MERTK, while only liposomes induced high C1QA and LC3 expression. Analysis of pro- and anti-inflammatory cytokines clearly indicated a shift towards tolerance induced by liposomal or apoptotic cell stimulation. This is the first investigation into the direct tolerance-enhancing effects of phosphatidylglycerol-containing liposomes that have potential as drug delivery vehicles for antigen-specific immunotherapy against autoimmune diseases.