Kathrin Thiem1, Geerte Hoeke2,3, Enchen Zhou2,3, Anneke Hijmans1, Tom Houben4, Margien G Boels2,5, Isabel M Mol2,3, Esther Lutgens6,7, Ronit Shiri-Sverdlov4, Johan Bussink8, Thirumala D Kanneganti9, Mariëtte R Boon2,3, Rinke Stienstra1,10, Cees J Tack1, Patrick Cn Rensen2,3, Mihai G Netea1,11, Jimmy Fp Berbée2,3, Janna A van Diepen1. 1. Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands. 3. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. 4. Departments of Molecular Genetics, Human Biology and Surgery, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands. 5. Division of Nephrology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands. 6. Division of Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 7. Institute for Cardiovascular Prevention, Ludwig Maximilians University of Munich, Munich, Germany. 8. Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. 9. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. 10. Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. 11. Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
Abstract
BACKGROUND: C-type lectin receptors, including Dectin-2, are pattern recognition receptors on monocytes and macrophages that mainly recognize sugars and sugar-like structures present on fungi. Activation of C-type lectin receptors induces downstream CARD9 signalling, leading to the production of cytokines. We hypothesized that under hyperglycaemic conditions, as is the case in diabetes mellitus, glycosylated protein (sugar-like) structures activate C-type lectin receptors, leading to immune cell activation and increased atherosclerosis development. METHODS: Low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with bone marrow from control wild-type, Dectin-2-/- or Card9-/- mice. After 6 weeks of recovery, mice received streptozotocin injections (50 mg/g BW; 5 days) to induce hyperglycaemia. After an additional 2 weeks, mice were fed a Western-type diet (0.1% cholesterol) for 10 weeks. RESULTS AND CONCLUSION: Deletion of haematopoietic Dectin-2 reduced the number of circulating Ly6Chi monocytes, increased pro-inflammatory cytokine production, but did not affect atherosclerosis development. Deletion of haematopoietic CARD9 tended to reduce macrophage and collagen content in atherosclerotic lesions, again without influencing the lesion size. Deletion of haematopoietic Dectin-2 did not influence atherosclerosis development under hyperglycaemic conditions, despite some minor effects on inflammation. Deletion of haematopoietic CARD9 induced minor alterations in plaque composition under hyperglycaemic conditions, without affecting lesion size.
BACKGROUND: C-type lectin receptors, including Dectin-2, are pattern recognition receptors on monocytes and macrophages that mainly recognize sugars and sugar-like structures present on fungi. Activation of C-type lectin receptors induces downstream CARD9 signalling, leading to the production of cytokines. We hypothesized that under hyperglycaemic conditions, as is the case in diabetes mellitus, glycosylated protein (sugar-like) structures activate C-type lectin receptors, leading to immune cell activation and increased atherosclerosis development. METHODS:Low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with bone marrow from control wild-type, Dectin-2-/- or Card9-/- mice. After 6 weeks of recovery, mice received streptozotocin injections (50 mg/g BW; 5 days) to induce hyperglycaemia. After an additional 2 weeks, mice were fed a Western-type diet (0.1% cholesterol) for 10 weeks. RESULTS AND CONCLUSION: Deletion of haematopoietic Dectin-2 reduced the number of circulating Ly6Chi monocytes, increased pro-inflammatory cytokine production, but did not affect atherosclerosis development. Deletion of haematopoietic CARD9 tended to reduce macrophage and collagen content in atherosclerotic lesions, again without influencing the lesion size. Deletion of haematopoietic Dectin-2 did not influence atherosclerosis development under hyperglycaemic conditions, despite some minor effects on inflammation. Deletion of haematopoietic CARD9 induced minor alterations in plaque composition under hyperglycaemic conditions, without affecting lesion size.