title: Hematopoietic α7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis.
abstract: BACKGROUND
  The autonomic nervous system attenuates inflammation through activation of the α7 nicotinic acetylcholine receptor (α7nAChR), a pathway termed the cholinergic anti-inflammatory reflex. Interestingly, α7nAChR is expressed on immune cells and platelets, both of which play a crucial role in the development of atherosclerosis.
  
  
  OBJECTIVE
  To investigate the role of hematopoietic α7nAChR in inflammation and platelet function in atherosclerotic ldlr(-/-) mice and to identify its consequences for atherosclerotic lesion development.
  
  
  METHODS
  Bone marrow from α7nAChR(-/-) mice or wild-type littermates was transplanted into irradiated ldlr(-/-) mice. After a recovery period of 8 weeks, the mice were fed an atherogenic Western-type diet for 7 weeks.
  
  
  RESULTS
  Hematopoietic α7nAChR deficiency clearly increased the number of leukocytes in the peritoneum (2.6-fold, P < 0.001), blood (2.9-fold; P < 0.01), mesenteric lymph nodes (2.0-fold; P < 0.001) and spleen (2.2-fold; P < 0.01), indicative of an increased inflammatory status. Additionally, expression of inflammatory mediators was increased in peritoneal leukocytes (TNFα, 1.6-fold, P < 0.01; CRP, 1.8-fold, P < 0.01) as well as in the spleen (TNFα, 1.6-fold, P < 0.01). The lack of α7nAChR on platelets from these mice increased the expression of active integrin αIIb β3 upon stimulation by ADP (1.9-fold, P < 0.01), indicating increased activation status, while incubation of human platelets with an α7nAChR agonist decreased aggregation (-35%, P < 0.05). Despite the large effects of hematopoietic α7nAChR deficiency on inflammatory status and platelet function, it did not affect atherosclerosis development or composition of lesions.
  
  
  CONCLUSIONS
  Hematopoietic α7nAChR is important for attenuation of inflammatory responses and maintaining normal platelet reactivity, but loss of hematopoietic α7nAChR does not aggravate development of atherosclerosis.
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Kooijman
authors.forename: I
authors.initials: I
authors.lastname: Meurs
authors.forename: M
authors.initials: M
authors.lastname: van der Stoep
authors.forename: K L
authors.initials: KL
authors.lastname: Habets
authors.forename: B
authors.initials: B
authors.lastname: Lammers
authors.forename: J F P
authors.initials: JF
authors.lastname: Berbée
authors.forename: L M
authors.initials: LM
authors.lastname: Havekes
authors.forename: M
authors.initials: M
authors.lastname: van Eck
authors.forename: J A
authors.initials: JA
authors.lastname: Romijn
authors.forename: S J A
authors.initials: SJ
authors.lastname: Korporaal
authors.forename: P C N
authors.initials: PC
authors.lastname: Rensen
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D066273:Diet, Western; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007249:Inflammation / Q000097:blood / Q000209:etiology* / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood; D007962:Leukocytes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D010972:Platelet Activating Factor; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000172:deficiency* / Q000235:genetics
chemical_list: C579166:Chrna7 protein, mouse; D018836:Inflammation Mediators; D010972:Platelet Activating Factor; D011973:Receptors, LDL; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: alpha7 nicotinic acetylcholine receptor; atherosclerosis; bone marrow transplantation; inflammation; platelets