Suppression of phagocytic function and phospholipid metabolism in macrophages by phosphatidylinositol liposomes.

Abstract

Increased phagocytosis of complement-opsonized vesicles was accompanied by increased phosphatidylinositol (Ptdlns) turnover in murine macrophages. However when PtdIns was also present as one of the lipids in the opsonized liposomes, it reduced both phagocytosis and stimulation of endogenous Ptdlns turnover. These suppressive effects did not occur with liposomes containing PtdIns phosphate (PtdIns-P). When a monoclonal IgM "anti-PtdIns-P" antibody that bound to inositol phosphate was substituted for antigalactosyl ceramide antibodies for activating complement in the opsonizing process, eflhanced phagocytosis occurred normally but increased cellular PtdIns turnover did not occur. Therefore the data show that, although PtdIns-P cannot replace PtdIns for suppressing Ptdlns turnover, Ptdlns-P can be induced to be suppressive after specific binding to an antibody that recognizes inositol phosphate. We conclude that ingestion of complement-opsonized liposomes by macrophages and complement-induced turnover of cellular PtdIns are separate but related phenomena that can be independently modulated by the polar group of liposomal Ptdlns.In 1953 Hokin and Hokin (1) observed that acetylcholine caused an enhancement of phosphatidylinositol (Ptdlns) metabolism in pancreatic slices. This suggested that Ptdlns might have a special function in the cell response to external stimulation by acetylcholine. Since that initial observation, "PtdIns responses" (enhanced PtdIns turnover) have been reported in a wide variety of tissues and cells and have been correlated with numerous stimuli modulating different cell functions (reviewed in refs. 2-7). Despite the voluminous literature in this field, the molecular basis of the PtdIns response, as well as its exact mechanism and function, have not been completely elucidated (2-7).The original purpose of the present study was to determine whether a Ptdlns response would appear during the course of complement-opsonized phagocytosis of liposomes. It was felt that this observation would be a natural step in a continuing investigation of complement-induced ingestion of liposomes by macrophages (8). Although a PtdIns response was indeed found, in the course of this work we also made a surprising discovery that the PtdIns response was exquisitely sensitive to the presence of exogenous PtdIns in the opsonized liposomes and the PtdIns response was suppressed when the liposomes contained Ptdlns. It occurred to us that this observation might have broad implications because PtdIns that is initially external to the cell had not been used previously to study modulation of intracellular Ptdlns turnover.In this paper we report (i) that both phagocytosis of liposomes and intracellular PtdIns turnover are enhanced by complement opsonization of the liposomes, (ii) that incubation of liposomal PtdIns with macrophages strongly suppresses both the phagocytosis of complement-opsonized liposomes and intracellular PtdIns turnover, and (iii) that complement-induced phagocytosis and increased PtdIns turnover in...

Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

“…In addition, the immunomodulatory effects of PI could also likely to play a significant role. In terms of effects upon immune cells, PI has been shown to suppress phagocytic function in macrophages (54) and could exert an inhibitory effect on lymphocyte activity (55). However, PI effect on dendritic dells, a primary initiator of T cell responses, is not clearly understood.…”

Phosphatidylinositides Bind to Plasma Membrane CD14 and Can Prevent Monocyte Activation by Bacterial Lipopolysaccharide

“…A great excess of PtdIns is required to inhibit LPS binding to mCD14, however, and very little is known about the movement of PtdIns between cells, lipoproteins, and other carrier molecules in blood. mCD14-bound phosphatidylinositides might also be translocated into the cell to participate in signaling reactions, to provide a source of intracellular arachidonate (35), or for other functions (23,36). Identifying mCD14 as a phosphatidylinositide and PS receptor raises intriguing questions about the possible functions of a LBP-dependent mechanism by which myeloid cells can bind these extracellular phospholipids.…”

“…The ability of macrophages to take up phospholipid-rich liposomes has been appreciated for many years (18,19), and recent reports indicate that both PtdIns and PS can bind to members of the class B scavenger receptor family (SR-BI/ CLA-1, CD36) (20,21), which are found on monocytes and macrophages. Certain lymphocyte subsets are also known to bind both PtdIns-and PS-containing liposomes with high affinity (22), and there is evidence that extracellular PtdIns can modulate macrophage functions such as phagocytosis (23). A role for lipid transfer proteins in these phenomena has not been described.…”

CD14-dependent Internalization and Metabolism of Extracellular Phosphatidylinositol by Monocytes

“…Having a mechanism for acquiring extracellular PtdIns may thus endow mCD14-expressing cells with the ability to supplement their existing PtdIns and arachidonate stores. In keeping with this notion, incubation with liposomes containing PtdIns suppressed stimulus-induced PtdIns turnover (biosynthesis) in mouse macrophages (21).…”