Myeloid Cell Specific ABCA1 Deletion Protects Mice From Bacterial Infection
Rationale: ATP-binding cassette transporter A1 (ABCA1) plays a critical role in eliminating excess free cholesterol (FC) from tissues by effluxing cellular FC and phospholipids to lipid-poor apolipoprotein A-I. Macrophage ABCA1 also dampens pro-inflammatory MyD88-dependent Toll-like receptor signaling by reducing cellular membrane FC and lipid raft content, indicating a role of ABCA1 in innate immunity. However, whether ABCA1 expression has a role in regulating macrophage function in vivo is unknown.
Objective: We investigated whether macrophage ABCA1 expression impacts host defense function, including microbial killing and chemotaxis.
Methods and Results: Myeloid cell-specific ABCA1 knockout (MSKO) vs. wild type (WT) mice were infected with Listeria monocytogenes (Lm) for 36h or 72h before sacrifice. Lm-induced monocytosis was similar for WT 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 post infection. In addition, Lm-infected MSKO mouse livers had: 1) greater MCP-1 and MIP-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 LPS in vivo. Lm infection of WT macrophages markedly reduced expression of ABCA1 protein as well as other cholesterol export proteins (such as ABCG1 and apoE).
Conclusions: Myeloid-specific ABCA1 deletion favors host response to and clearance of Lm. Macrophage Lm infection reduces expression of cholesterol export proteins, suggesting that diminished cholesterol efflux enhances innate immune function of macrophages.
- Received March 10, 2012.
- Accepted September 6, 2012.
- Copyright © 2012, American Heart Association