title: Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions.
abstract: BACKGROUND
  Atherosclerotic lesions are believed to grow via the recruitment of bone marrow-derived monocytes. Among the known murine monocyte subsets, Ly-6C(high) monocytes are inflammatory, accumulate in lesions preferentially, and differentiate. Here, we hypothesized that the bone marrow outsources the production of Ly-6C(high) monocytes during atherosclerosis.
  
  
  RESULTS
  Using murine models of atherosclerosis and fate-mapping approaches, we show that hematopoietic stem and progenitor cells progressively relocate from the bone marrow to the splenic red pulp, where they encounter granulocyte macrophage colony-stimulating factor and interleukin-3, clonally expand, and differentiate to Ly-6C(high) monocytes. Monocytes born in such extramedullary niches intravasate, circulate, and accumulate abundantly in atheromata. On lesional infiltration, Ly-6C(high) monocytes secrete inflammatory cytokines, reactive oxygen species, and proteases. Eventually, they ingest lipids and become foam cells.
  
  
  CONCLUSIONS
  Our findings indicate that extramedullary sites supplement the hematopoietic function of the bone marrow by producing circulating inflammatory cells that infiltrate atherosclerotic lesions.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Simches Research Bldg, 185 Cambridge St, Boston, MA 02114, USA. robbins.clinton@mgh.harvard.edu
authors.forename: Clinton S
authors.initials: CS
authors.lastname: Robbins
authors.forename: Aleksey
authors.initials: A
authors.lastname: Chudnovskiy
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Rauch
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Rostic
authors.initials: R
authors.lastname: Gorbatov
authors.forename: Martin
authors.initials: M
authors.lastname: Etzrodt
authors.forename: Georg F
authors.initials: GF
authors.lastname: Weber
authors.forename: Takuya
authors.initials: T
authors.lastname: Ueno
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Mulligan-Kehoe
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Pittet
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology*; D001853:Bone Marrow; D002454:Cell Differentiation; D002465:Cell Movement / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006411:Hematopoiesis, Extramedullary / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000473:pathology; D007249:Inflammation; D007377:Interleukin-3; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000473:pathology*
chemical_list: D000950:Antigens, Ly; D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor