Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis

Dragana Dragoljevic, Michael J. Kraakman, Prabhakara R. Nagareddy, Devi Ngo, Waled Shihata, Helene L. Kammoun, Alexandra Whillas, Man Kit Sam Lee, Annas Al-Sharea, Gerard Pernes, Michelle C. Flynn, Graeme I. Lancaster, Mark A. Febbraio, Jaye Chin-Dusting, Beatriz Y. Hanaoka, Ian P. Wicks, Andrew J. Murphy

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)2158-2167
Number of pages11
JournalEuropean Heart Journal
Volume39
Issue number23
DOIs
Publication statusPublished - 14 Jun 2018

Keywords

  • Atherosclerosis
  • Cellular cholesterol defects
  • Enhanced haematopoiesis
  • Rheumatoid arthritis

Cite this

Dragoljevic, Dragana ; Kraakman, Michael J. ; Nagareddy, Prabhakara R. ; Ngo, Devi ; Shihata, Waled ; Kammoun, Helene L. ; Whillas, Alexandra ; Lee, Man Kit Sam ; Al-Sharea, Annas ; Pernes, Gerard ; Flynn, Michelle C. ; Lancaster, Graeme I. ; Febbraio, Mark A. ; Chin-Dusting, Jaye ; Hanaoka, Beatriz Y. ; Wicks, Ian P. ; Murphy, Andrew J. / Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis. In: European Heart Journal. 2018 ; Vol. 39, No. 23. pp. 2158-2167.
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title = "Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis",
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.",
keywords = "Atherosclerosis, Cellular cholesterol defects, Enhanced haematopoiesis, Rheumatoid arthritis",
author = "Dragana Dragoljevic and Kraakman, {Michael J.} and Nagareddy, {Prabhakara R.} and Devi Ngo and Waled Shihata and Kammoun, {Helene L.} and Alexandra Whillas and Lee, {Man Kit Sam} and Annas Al-Sharea and Gerard Pernes and Flynn, {Michelle C.} and Lancaster, {Graeme I.} and Febbraio, {Mark A.} and Jaye Chin-Dusting and Hanaoka, {Beatriz Y.} and Wicks, {Ian P.} and Murphy, {Andrew J.}",
year = "2018",
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doi = "10.1093/eurheartj/ehy119",
language = "English",
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Dragoljevic, D, Kraakman, MJ, Nagareddy, PR, Ngo, D, Shihata, W, Kammoun, HL, Whillas, A, Lee, MKS, Al-Sharea, A, Pernes, G, Flynn, MC, Lancaster, GI, Febbraio, MA, Chin-Dusting, J, Hanaoka, BY, Wicks, IP & Murphy, AJ 2018, 'Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis' European Heart Journal, vol. 39, no. 23, pp. 2158-2167. https://doi.org/10.1093/eurheartj/ehy119

Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis. / Dragoljevic, Dragana; Kraakman, Michael J.; Nagareddy, Prabhakara R.; Ngo, Devi; Shihata, Waled; Kammoun, Helene L.; Whillas, Alexandra; Lee, Man Kit Sam; Al-Sharea, Annas; Pernes, Gerard; Flynn, Michelle C.; Lancaster, Graeme I.; Febbraio, Mark A.; Chin-Dusting, Jaye; Hanaoka, Beatriz Y.; Wicks, Ian P.; Murphy, Andrew J.

In: European Heart Journal, Vol. 39, No. 23, 14.06.2018, p. 2158-2167.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis

AU - Dragoljevic, Dragana

AU - Kraakman, Michael J.

AU - Nagareddy, Prabhakara R.

AU - Ngo, Devi

AU - Shihata, Waled

AU - Kammoun, Helene L.

AU - Whillas, Alexandra

AU - Lee, Man Kit Sam

AU - Al-Sharea, Annas

AU - Pernes, Gerard

AU - Flynn, Michelle C.

AU - Lancaster, Graeme I.

AU - Febbraio, Mark A.

AU - Chin-Dusting, Jaye

AU - Hanaoka, Beatriz Y.

AU - Wicks, Ian P.

AU - Murphy, Andrew J.

PY - 2018/6/14

Y1 - 2018/6/14

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Cellular cholesterol defects

KW - Enhanced haematopoiesis

KW - Rheumatoid arthritis

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U2 - 10.1093/eurheartj/ehy119

DO - 10.1093/eurheartj/ehy119

M3 - Article

VL - 39

SP - 2158

EP - 2167

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 23

ER -