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Hematopoietic α7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis

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Author: Kooijman, S. · Meurs, I. · Stoep, M. van der · Habets, K.L. · Lammers, B. · Berbée, J.F.P. · Havekes, L.M. · Eck, M. van · Romijn, J.A. · Korporaal, S.J.A. · Rensen, P.C.N.
Type:article
Date:2015
Source:Journal of Thrombosis and Haemostasis, 1, 13, 126-135
Identifier: 522519
doi: doi:10.1111/jth.12765
Keywords: Biology · Alpha7 nicotinic acetylcholine receptor · Atherosclerosis · Bone marrow transplantation · Inflammation · Platelets · Bungarotoxin receptor · C reactive protein · Tumor necrosis factor alpha · Animal experiment · Animal model · Atherogenic diet · Controlled study · Disease course · Leukocyte · Mesentery lymph node · Mouse · Nonhuman · Peritoneum · Spleen · Thrombocyte activation · Thrombocyte function · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences

Abstract

Summary: 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.