Mature Dendritic Cell Generation Promoted by Lysophosphatidylcholine

Abstract

During the acute phase response the interplay between high density lipoproteins and low density lipoproteins (LDL) favors transient generation of oxidized LDL with proinflammatory activities. We hypothesized that oxidative modification of LDL is an endogenous signal for the immune system and have shown that oxidized LDL promotes mature dendritic cell transition from monocyte therefore linking the non specific acute phase response to adaptive immunity. Lysophosphatidylcholine (LPC) is a major lipid component of oxidized LDL with reported proinflammatory activities. We now report that LPC acts through G protein-coupled receptors on differentiating monocytes to generate mature dendritic cells with the ability to stimulate IL-2 and IFNγ production by allogeneic T lymphocytes. LPC is most effective in lipoprotein deprived serum and can be inhibited by an excess of native LDL reflecting normal plasma conditions. Therefore, by controlling the balance between native and oxidized lipoproteins and the resulting production of LPC, the acute phase reactants may provide a context of antigen presentation which is transiently favorable to immune activation. Intralipid, a therapeutic lipid emulsion for parenteral nutrition with unexplained immunomodulatory properties, also blocked LPC activity. This opens perspectives for the understanding and treatment of acute and chronic inflammatory diseases.

Lysophosphatidylcholine is a natural adjuvant that initiates cellular immune responses

“…Indeed, acute phase lipoproteins can be submitted to biochemical modifications that lead to the production of bioactive molecules. Among these molecules, LPC is known to be a pro-inflammatory lysophospholipid and to stimulate the generation of mature DC from differentiating monocytes in vitro [8]. This raised the Alum is associated with a Th2-oriented immune response characterized by a strong humoral response but a poor cellular immunity.…”

“…The following experiments were designed to explore the ability of LPC to prime Ag-specific In previous reports, we showed that the action of LPC on DC in vitro could be blocked by Intralipid (IL), a therapeutic lipid emulsion currently used for parenteral nutrition in case of septic shock [8]. Figure 1C shows that co-injection of IL with HEL+LPC strongly inhibited the induction of the HEL-specific T cell response, indicating that IL can antagonize in vivo the immunostimulating effect of LPC.…”

“…It is accompanied by alterations in lipoprotein composition that result in generation of oxidized low density lipoprotein (oxLDL) and oxidized phospholipids [3,4]. OxLDL were first studied for their role in chronic inflammation during atherosclerosis [5] but recent work indicates that infection and inflammation also result in increased levels of oxLDL [6] and modified lipids that can be detected by the immune system [7][8][9].…”

“…LPC also displays some immunoregulatory activities. We recently reported that LPC acts through G protein-coupled receptors on differentiating monocytes to generate mature DC with the ability to stimulate IL-2 and IFNγ production by allogeneic T lymphocytes [8]. PPARγ are involved in this phenomenon but it is not clear whether the action of LPC on these nuclear receptors is direct or not [9].…”

“…Sensing the danger is a crucial function of Ag-presenting cells, that is necessary to initiate primary immune responses [35,36]. We previously hypothesized that oxLDL and modified phospholipids such as LPC generated during APR could signal the presence of a dangerous situation to the immune system and showed that oxLDL and LPC could favour the development of adaptive immunity by promoting mature DC generation in vitro [7][8][9]. It is shown here that LPC can prime both cellular and humoral Ag-specific responses, confirming that the APR regulates the production of critical immunoregulatory molecules by controlling the biochemical composition of lipoproteins.…”