TY - JOUR
T1 - Hematopoietic α7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis
AU - Kooijman, Sander
AU - Meurs, I.
AU - van der Stoep, M.
AU - Habets, K. L.
AU - Lammers, B.
AU - Berbée, J. F P
AU - Havekes, L. M.
AU - van Eck, M.
AU - Romijn, J. A.
AU - Korporaal, S. J A
AU - Rensen, P. C N
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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 αIIbβ3 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.
AB - 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 αIIbβ3 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.
KW - Alpha7 nicotinic acetylcholine receptor
KW - Atherosclerosis
KW - Bone marrow transplantation
KW - Inflammation
KW - Platelets
UR - http://www.scopus.com/inward/record.url?scp=84920970050&partnerID=8YFLogxK
U2 - 10.1111/jth.12765
DO - 10.1111/jth.12765
M3 - Article
C2 - 25345495
AN - SCOPUS:84920970050
SN - 1538-7933
VL - 13
SP - 126
EP - 135
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 1
ER -