title: Myeloid cell-specific ABCA1 deletion protects mice from bacterial infection.
abstract: BACKGROUND
  ATP-binding cassette transporter A1 (ABCA1) plays a critical role in eliminating excess free cholesterol from tissues by effluxing cellular free cholesterol and phospholipids to lipid-poor apolipoprotein AI. Macrophage ABCA1 also dampens proinflammatory myeloid differentiation primary-response protein 88-dependent toll-like receptor signaling by reducing cellular membrane free cholesterol 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.
  
  
  RESULTS
  Myeloid cell-specific ABCA1 knockout (MSKO) vs wild-type mice were infected with 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).
  
  
  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.
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Zhu
authors.forename: Marlena M
authors.initials: MM
authors.lastname: Westcott
authors.forename: Xin
authors.initials: X
authors.lastname: Bi
authors.forename: Mingxia
authors.initials: M
authors.lastname: Liu
authors.forename: Kymberly M
authors.initials: KM
authors.lastname: Gowdy
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Seo
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.forename: Abraham K
authors.initials: AK
authors.lastname: Gebre
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Hiltbold
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Hitbold
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018925:Chemokines / Q000097:blood / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000276:immunology; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology* / Q000502:physiology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D008099:Liver / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018925:Chemokines; D016207:Cytokines