Dragana Dragoljevic1,2, Michael J Kraakman1,3, Prabhakara R Nagareddy4, Devi Ngo5, Waled Shihata1,6, Helene L Kammoun1,2, Alexandra Whillas1, Man Kit Sam Lee1,2, Annas Al-Sharea1,2, Gerard Pernes1,2, Michelle C Flynn1,2, Graeme I Lancaster1,2, Mark A Febbraio7, Jaye Chin-Dusting6, Beatriz Y Hanaoka8, Ian P Wicks5,9, Andrew J Murphy1,2. 1. Haematopoiesis and Leukocyte Biology Laboratory, Division of Immunometabolism, Baker Heart and Diabetes Institute, 75 Commercial Rd, 3004 Melbourne, Victoria, Australia. 2. Department of Immunology, Monash University, 89 Commercial Road, 3004 Melbourne, Victoria, Australia. 3. Human Nutrition, Naomi Berrie Diabetes Centre, Columbia University, New York, 1150 St Nicholas Ave, 10032 NY, USA. 4. Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, 1720 2nd Ave South, 35294 AL, USA. 5. Inflammation Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, 3052 Melbourne, Victoria, Australia. 6. Department of Pharmacology, Monash University, Wellington Road, 3800 Clayton, Victoria, Australia. 7. Cellular and Molecular Metabolism, Division of Diabetes & Metabolism, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010 Sydney, New South Wales, Australia. 8. Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, 1720 2nd Ave South, 35294 AL, USA. 9. Rheumatology Unit, Royal Melbourne Hospital, 300 Grattan St, 3050 Melbourne, Victoria, Australia.
Abstract
Aim: Rheumatoid arthritis (RA) is associated with an approximately two-fold elevated risk of cardiovascular (CV)-related mortality. Patients with RA present with systemic inflammation including raised circulating myeloid cells, but fail to display traditional CV risk-factors, particularly dyslipidaemia. We aimed to explore if increased circulating myeloid cells is associated with impaired atherosclerotic lesion regression or altered progression in RA. Methods and results: Using flow cytometry, we noted prominent monocytosis, neutrophilia, and thrombocytosis in two mouse models of RA. This was due to enhanced proliferation of the haematopoietic stem and progenitor cells (HSPCs) in the bone marrow and the spleen. HSPCs expansion was associated with an increase in the cholesterol content, due to a down-regulation of cholesterol efflux genes, Apoe, Abca1, and Abcg1. The HSPCs also had enhanced expression of key myeloid promoting growth factor receptors. Systemic inflammation was found to cause defective cellular cholesterol metabolism. Increased myeloid cells in mice with RA were associated with a significant impairment in lesion regression, even though cholesterol levels were equivalent to non-arthritic mice. Lesions from arthritic mice exhibited a less stable phenotype as demonstrated by increased immune cell infiltration, lipid accumulation, and decreased collagen formation. In a progression model, we noted monocytosis, enhanced monocytes recruitment to lesions, and increased plaque macrophages. This was reversed with administration of reconstituted high-density lipoprotein (rHDL). Furthermore, RA patients have expanded CD16+ monocyte subsets and a down-regulation of ABCA1 and ABCG1. Conclusion: Rheumatoid arthritis impairs atherosclerotic regression and alters progression, which is associated with an expansion of myeloid cells and disturbed cellular cholesterol handling, independent of plasma cholesterol levels. Infusion of rHDL prevented enhanced myelopoiesis and monocyte entry into lesions. Targeting cellular cholesterol defects in people with RA, even if plasma cholesterol is within the normal range, may limit vascular disease.
Aim: Rheumatoid arthritis (RA) is associated with an approximately two-fold elevated risk of cardiovascular (CV)-related mortality. Patients with RA present with systemic inflammation including raised circulating myeloid cells, but fail to display traditional CV risk-factors, particularly dyslipidaemia. We aimed to explore if increased circulating myeloid cells is associated with impaired atherosclerotic lesion regression or altered progression in RA. Methods and results: Using flow cytometry, we noted prominent monocytosis, neutrophilia, and thrombocytosis in two mouse models of RA. This was due to enhanced proliferation of the haematopoietic stem and progenitor cells (HSPCs) in the bone marrow and the spleen. HSPCs expansion was associated with an increase in the cholesterol content, due to a down-regulation of cholesterol efflux genes, Apoe, Abca1, and Abcg1. The HSPCs also had enhanced expression of key myeloid promoting growth factor receptors. Systemic inflammation was found to cause defective cellular cholesterol metabolism. Increased myeloid cells in mice with RA were associated with a significant impairment in lesion regression, even though cholesterol levels were equivalent to non-arthritic mice. Lesions from arthritic mice exhibited a less stable phenotype as demonstrated by increased immune cell infiltration, lipid accumulation, and decreased collagen formation. In a progression model, we noted monocytosis, enhanced monocytes recruitment to lesions, and increased plaque macrophages. This was reversed with administration of reconstituted high-density lipoprotein (rHDL). Furthermore, RApatients have expanded CD16+ monocyte subsets and a down-regulation of ABCA1 and ABCG1. Conclusion:Rheumatoid arthritis impairs atherosclerotic regression and alters progression, which is associated with an expansion of myeloid cells and disturbed cellular cholesterol handling, independent of plasma cholesterol levels. Infusion of rHDL prevented enhanced myelopoiesis and monocyte entry into lesions. Targeting cellular cholesterol defects in people with RA, even if plasma cholesterol is within the normal range, may limit vascular disease.
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