Myeloid Cell − Specific ABCA 1 Deletion Protects Mice From Bacterial Infection

A TP-binding cassette transporter A1 (ABCA1) is a plasma membrane protein that functions to eliminate excess free cholesterol (FC) from tissues by effluxing cellular FC and phospholipids to lipid-free apolipoprotein AI, forming nascent high-density lipoprotein particles. 1,2 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 high-density lipoprotein cholesterol concentrations, mildly elevated plasma triglyceride levels, and accumulation of cholesterol in macrophages. 3–5 ABCA1 protein is widely expressed in most cells in the body, and its expression is regulated by transcriptional activation and protein degradation. Generation of cell-specific Abca1 knockout mice has helped define the role of cell-specific ABCA1 expression in whole-body high-density lipoprotein biogenesis, as well as several unanticipated roles for the transporter. For example, hepato-cyte and intestinal epithelial cell ABCA1 contribute 70% to 80% and 20% to 30% of the plasma high-density lipoprotein pool, respectively. Pancreatic β-cell ABCA1 plays a role in insulin secretion 10 and brain ABCA1 regulates neuronal structure and function. 11 Macrophages protect the host against exogenous and en-dogenous dangers by killing invading microbes and phago-cytosing apoptotic or dead cells, thereby acting as one of the primary immune cell types involved in innate immunity. To explore the specific role of ABCA1 in macrophages, we generated myeloid cell–specific ABCA1 knockout (MSKO) mice. 12 Using this unique mouse model, we demonstrated that Objective: We investigated whether macrophage ABCA1 expression impacts host defense function, including microbial killing and chemotaxis. Listeria monocytogenes (Lm) for 36 hours or 72 hours before euthanasia. Lm-induced monocytosis was similar for wild-type and MSKO mice; however, MSKO mice were more resistant to Lm infection, with significantly less body weight loss, less Lm burden in liver and spleen, and less hepatic damage 3 days postinfection. In addition, Lm-infected MSKO mouse livers had: (1) greater monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 expression; (2) more monocyte/macrophage infiltration; (3) less neutral lipid accumulation; and (4) diminished expression of lipogenic genes. MSKO macrophages showed enhanced chemotaxis toward chemokines in vitro and increased migration from peritoneum in response to lipopolysaccharide in vivo. Lm infection of wild-type macrophages markedly reduced expression of ABCA1 protein, as well as other cholesterol export proteins (such as ATP-binding cassette transporter G1 and apolipoprotein E). infection reduces expression of cholesterol export proteins, suggesting that …

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