title: RP105 deficiency attenuates early atherosclerosis via decreased monocyte influx in a CCR2 dependent manner.
abstract: OBJECTIVE
  Toll like receptor 4 (TLR4) plays a key role in inflammation and previously it was established that TLR4 deficiency attenuates atherosclerosis. RadioProtective 105 (RP105) is a structural homolog of TLR4 and an important regulator of TLR4 signaling, suggesting that RP105 may also be an important effector in atherosclerosis. We thus aimed to determine the role of RP105 in atherosclerotic lesion development using RP105 deficient mice on an atherosclerotic background.
  
  
  RESULTS
  Atherosclerosis was induced in Western-type diet fed low density lipoprotein receptor deficient (LDLr(-/-)) and LDLr/RP105 double knockout (LDLr(-/-)/RP105(-/-)) mice by means of perivascular carotid artery collar placement. Lesion size was significantly reduced by 58% in LDLr(-/-)/RP105(-/-) mice, and moreover, plaque macrophage content was markedly reduced by 40%. In a model of acute peritonitis, monocyte influx was almost 3-fold reduced in LDLr(-/-)/RP105(-/-) mice (P = 0.001), while neutrophil influx remained unaltered, suggestive of an altered migratory capacity of monocytes upon deletion of RP105. Interestingly, in vitro stimulation of monocytes with LPS induced a downregulation of CCR2, a chemokine receptor crucially involved in monocyte influx to atherosclerotic lesions, which was more pronounced in LDLr(-/-)/RP105(-/-) monocytes as compared to LDLr(-/-) monocytes.
  
  
  CONCLUSIONS
  We here show that RP105 deficiency results in reduced early atherosclerotic plaque development with a marked decrease in lesional macrophage content, which may be due to disturbed migration of RP105 deficient monocytes resulting from CCR2 downregulation.
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Wezel
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Daniël
authors.initials: D
authors.lastname: van der Velden
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Maassen
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: H Maxime
authors.initials: HM
authors.lastname: Lagraauw
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jacco C
authors.initials: JC
authors.lastname: Karper
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: p.h.a.quax@lumc.nl.
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
mesh_terms: D000821:Animal Feed; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D050197:Atherosclerosis / Q000235:genetics* / Q000503:physiopathology; D001402:B-Lymphocytes / Q000166:cytology; D001853:Bone Marrow / Q000473:pathology; D002465:Cell Movement; D003433:Crosses, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007073:Immunoglobulin E / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology*; D010538:Peritonitis / Q000235:genetics / Q000503:physiopathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; C515335:Ccr2 protein, mouse; D007075:Immunoglobulin M; C490500:Ly78 protein, mouse; D054390:Receptors, CCR2; D011973:Receptors, LDL; D007073:Immunoglobulin E
keywords: Atherosclerosis; CCR2; Monocyte migration; RP105; TLR4