title: CD11b+Gr-1+ myeloid-derived suppressor cells reduce atherosclerotic lesion development in LDLr deficient mice.
abstract: Myeloid-derived suppressor cells (MDSCs) form a heterogeneous population of cells composed of early myeloid progenitor cells and immature myeloid cells, which strongly suppress pro-inflammatory immune cells in inflammatory diseases. Currently, it is unknown whether MDSCs contribute to atherosclerosis, a chronic inflammatory disease in which accumulation of lipoproteins in the arterial wall activates the immune system causing abnormal vascular remodelling and vessel occlusion. Here, we investigated whether and how MDSCs contribute to the development of atherosclerosis.
  
  
  
  We show that MDSCs arise in the bone marrow of LDLr(-/-) mice during atherosclerosis and strongly suppress proliferation of T cells. Adoptive transfer of MDSCs into both female and male LDLr(-/-) mice fed a Western-type diet (WTD) ameliorates atherosclerosis with 35%. We observed a 54% reduction in adventitial T cells, and more specifically, MDSCs suppress Th1 and Th17 cells. In addition, treatment with MDSCs reduces circulating pro-atherogenic B2 cells. We found two subsets of MDSCs in the bone marrow of hypercholesterolemic mice, monocytic and granulocytic MDSCs (mo- and gr-MDSCs, respectively), of which the percentage of mo-MDSCs significantly increased during WTD feeding. Moreover, mo-MDSCs completely abolished splenocyte proliferation, whereas gr-MDSCs were unable to suppress proliferation. Mechanistically, we show that MDSCs from atherosclerotic mice suppress T cells in an IFN-γ- and nitric oxide-dependent manner, which is associated with the action of mo-MDSCs.
  
  
  
  This study demonstrates that MDSCs develop during atherosclerosis and reduce atherosclerosis via suppression of pro-inflammatory immune responses.
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands a.c.foks@lacdr.leidenuniv.nl.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Foks
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Gijs H M
authors.initials: GH
authors.lastname: Van Puijvelde
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Jolien
authors.initials: J
authors.lastname: Wolbert
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Mara J
authors.initials: MJ
authors.lastname: Kröner
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Frodermann
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Der Heijden
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van Santbrink
authors.affiliation: Bioceros BV, Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.affiliation: Division of Biopharmaceutics, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D039481:CD11b Antigen / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D066273:Diet, Western; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D018345:Mice, Knockout; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D009569:Nitric Oxide / Q000378:metabolism; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C480309:Ly6G antigen, mouse; D011973:Receptors, LDL; D009569:Nitric Oxide; D007371:Interferon-gamma
keywords: Atherosclerosis; Immunology; Immunosuppressive therapy; MDSCs; T cells