Macrophage-specific Abca1 knock-out (Abca1؊M/؊M ) mice were generated to determine the role of macrophage ABCA1 expression in plasma lipoprotein concentrations and the innate immune response of macrophages. Plasma lipid and lipoprotein concentrations in chow-fed Abca1 ؊M/؊M and wild-type (WT) mice were indistinguishable. Compared with WT macrophages, Abca1 ؊M/؊M macrophages had a >95% reduction in ABCA1 protein, failed to efflux lipid to apoA-I, and had a significant increase in free cholesterol (FC) and membrane lipid rafts without induction of endoplasmic reticulum stress. Lipopolysaccharide (LPS)-treated Abca1 ABCA1 (ATP-binding cassette transporter A1) is a plasma membrane protein that is widely expressed throughout the body (1, 2) and functions as a primary gatekeeper for eliminating excess free cholesterol (FC) 2 from tissues by effluxing cellular FC and phospholipid (PL) to lipid-free apoA-I, resulting in the formation of nascent high density lipoprotein (HDL) particles (3, 4). The nascent discoid-shaped HDL then undergoes a maturation process that involves additional lipid acquisition and conversion of FC to cholesteryl ester (CE) by lecithin:cholesterol acyltransferase to become mature spherical plasma HDL. Mutations that inactivate the human ABCA1 gene result in Tangier disease, which is characterized by extremely low HDL cholesterol concentrations, mildly elevated plasma trigelyceride levels, and accumulation of cholesterol in macrophages (5-10). Targeted deletion of Abca1 in mice and a natural mutation of Abca1 in the Wisconsin hypoalpha mutant chicken recapitulate the Tangier plasma lipid phenotype, supporting the essential role of ABCA1 in HDL formation (11-15). Although ABCA1 is expressed in many cells in the body, recent studies in hepatocyte-and intestinal epithelium-specific Abca1 knock-out mice suggest that the liver contributes 70 -80% of the plasma HDL pool, whereas the intestine contributes 20 -30% (16, 17). Although mobilization of excess FC from macrophages is dependent on ABCA1 and results in the formation of nascent HDL particles, transplantation of bone marrow from Abca1 knock-out (KO) mice into wild-type (WT) mice or transplantation of WT marrow into Abca1 KO recipients has little effect on plasma HDL concentrations, suggesting that macrophage ABCA1 expression has minimal impact on plasma HDL concentrations (18,19).Macrophages are a primary cell type involved in innate immunity. Although macrophage ABCA1 has a minimal impact on plasma lipid levels, there is evidence that its activity modulates the inflammatory response of macrophages to pathogen-associated molecules such as lipopolysaccharide
The plasma membranes of eukaryotic cells are not uniform and possess distinct cholesterol- and sphingolipid-rich raft microdomains that are enriched in proteins known to be essential for cellular function. Lipid raft microdomains are important for T cell receptor (TCR)-mediated activation of T cells. However, the importance of lipid rafts on antigen presenting cells (APCs) and their role in major histocompatibility (MHC) class II-restricted antigen presentation has not been examined. MHC class II molecules were found to be constitutively present in plasma membrane lipid rafts in B cells. Disruption of these microdomains dramatically inhibited antigen presentation at limiting concentrations of antigen. The inhibitory effect of raft disruption on antigen presentation could be overcome by loading the APCs with exceptionally high doses of antigen, showing that raft association concentrates MHC class II molecules into microdomains that allow efficient antigen presentation at low ligand densities.
ATP-binding cassette transporter A1 (ABCA1) is a plasma membrane protein that functions to eliminate excess free cholesterol (FC) from tissues by effl uxing cellular FC and phospholipid (PL) to lipid-free apolipoprotein AI, forming nascent HDL particles ( 1, 2 ). Therefore, ABCA1 plays a critical role in the movement of cholesterol from peripheral tissues to the liver in a process known as reverse cholesterol transport. Mutations that inactivate the human ABCA1 gene result in Tangier disease, which is characterized by extremely low plasma HDL cholesterol concentrations, mildly elevated plasma triglyceride levels, and accumulation of cholesterol in macrophages ( 3-5 ). ABCA1 protein is expressed to a variable extent in most cells in the body, and its expression is regulated by transcriptional activation and protein degradation ( 6, 7 ), making it diffi cult to determine HL-49373, HL-094525, and AT-27820 (J.S.P.) Ϫ / Ϫ , total Abca1 knockout; ABCG1, ATP-binding cassette transporter G1; BMDM, bone marrow-derived macrophage; CT-B, cholera toxin B; FC, free cholesterol; fPEG-chol, fl uorescein ester of polyethylene glycol-derivatized Macrophage ABCA1 reduces MyD88-dependent Toll-like This work was supported by National Institutes of Health Grants
Activation of CD4+ Th cells requires their cognate interaction with APCs bearing specific relevant MHC class II-peptide complexes. This cognate interaction culminates in the formation of an immunological synapse that contains the various proteins and lipids required for efficient T cell activation. We now show that APC lipid raft membrane microdomains contain specific class II-peptide complexes and serve as platforms that deliver these raft-associated class II molecules to the immunological synapse. APC rafts are required for T cell:APC conjugate formation and T cell activation at low densities of relevant class II-peptide complexes, a requirement that can be overcome at high class II-peptide density. Analysis of confocal microscopy images revealed that over time APC lipid rafts, raft-associated relevant class II-peptide complexes, and even immunologically irrelevant class II molecules accumulate at the immunological synapse. As the immunological synapse matures, relevant class II-peptide complexes are sorted to a central region of the interface, while irrelevant class II molecules are excluded from this site. We propose that T cell activation is facilitated by recruitment of MHC class II-peptide complexes to the immunological synapse by virtue of their constitutive association with lipid raft microdomains.
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