EDITORIAL COMMENT URRENT C OPINION
Atherosclerosis: cell biology and lipoproteins Harry Bjo¨rkbacka
The monocyte-derived macrophage foam cell has long been thought of as the archetypical cell in atherosclerotic lesions. Recent studies, however, indicate that many cells considered to be monocyte-derived macrophage foam cells have, in fact, a smooth muscle cell (SMC) origin. Other recent studies extend the concept of cellular plasticity to other vascular cells. It has long been recognized that SMCs can ingest lipids and contribute to foam cell formation in human atherosclerotic lesions [1]. SMCs undergo a phenotypic switch when they migrate from the media to the intima in atherosclerotic plaque formation, but how this process contributes to SMC foam cell formation is far from well understood, although in-vitro studies [2 ] have associated oxidized LDL-induced foam cell formation to phenotypic switching. Recently, Allahverdian et al. [3 ] found by analyzing foam cell-rich lesions in human coronary arteries from hearts explanted at the time of transplantation that as much as half of the foam cells were also a-smooth muscle actin positive. Given that large gene expression array studies have not found any evidence for a-smooth muscle actin expression in cells of the myeloid lineage and that a-smooth muscle actin staining likely underestimates the number of foam cells with SMC origin, as some intimal SMCs have been reported to express very little a-smooth muscle actin, the authors conclude that the majority of foam cells in human coronary atherosclerosis are likely SMC derived. The authors find that foam cells of SMC origin express less ATP-binding cassette transporter 1, sub-family A (ABCA1) than foam cells of myeloid origin, suggesting that reduced cholesterol trafficking could be the cause of cholesterol accumulation in foam cells of SMC origin. In support of the observational data in humans, Feil et al. [4 ] recently showed with elegant genetic fate mapping experiments in mice that medial SMCs can transdifferentiate to macrophage-like cells that make up a major constituent in advanced atherosclerotic lesions. The SMCs originally found in the media in young mice seemed to migrate to the intima in older atherosclerotic mice where they underwent clonal expansion to form large patches of SMCs with reduced or lost a-smooth muscle actin expression, while gaining expression of macrophage markers, &
&&
&&
such as CD68 and galectin-3. Interestingly, other vascular cells also display similar cellular plasticity. Ubil et al. [5 ] recently showed using genetic fate mapping in mice that fibroblast can act as a source of endothelial cells during cardiac injury and that these endothelial cells with a fibroblast origin have an important role in cardiac repair after ischemiareperfusion injury. Along the same lines, Sayed et al. [6 ] recently showed that Toll-like receptor 3 agonists in combination with endothelial cell growth factors can transdifferentiate human fibroblasts into endothelial cells that can reduce tissue injury in a mouse hind limb ischemia model. At the same time as the macrophage contribution to foam cells is put in question, the contribution of monocyte recruitment and subsequent differentiation into macrophages versus local proliferation of resident macrophages is being evaluated in cardiac ischemia and atherosclerosis. Monocytes have previously been shown [7] to make up a splenic reservoir that is quickly mobilized in response to ischemic myocardial injury. The monocyte progenitors that seed the spleen after an ischemic injury boost monocyte production that, subsequently, accelerates atherosclerosis and may explain why individuals suffering coronary events have a high risk of recurring events [8]. Recently, by putting mice in parabiosis with joint circulation, Heidt et al. [9 ] showed that monocytes replenish the dying or emigrating macrophage pool in the ischemic myocardium, whereas local proliferation of resident macrophages dominated the steady-state and chronic phase after myocardial infarction. In atherosclerotic lesions, macrophage accumulation is also dominated by local proliferation of macrophages rather than influx of monocytes; it has been shown [10,11] that monocytes undergoing extramedullary hematopoiesis in the spleen can accumulate and contribute to &
&
&&
Department of Clinical Sciences, Ska˚ne University Hospital, Lund University, Malmo¨, Sweden Correspondence to Harry Bjo¨rkbacka, Experimental Cardiovascular Research, CRC Lund University, Building 91:12, Jan Waldenstro¨ms gata 35, Malmo¨ University Hospital, SE-205 02 Malmo¨, Sweden. Tel: +46 0 40 391205; fax: +46 0 40 391212; e-mail: [email protected] Curr Opin Lipidol 2015, 26:67–69 DOI:10.1097/MOL.0000000000000150
0957-9672 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-lipidology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Bimonthly update Atherosclerosis: cell biology and lipoproteins
atherosclerotic lesion progression. Lately, Courties et al. [12 ] showed that ischemic stroke in mice activates hematopoietic stem cells leading to increased numbers of circulating myeloid cells, similar to what is often observed in stroke patients. Interestingly, increased signaling of the sympathetic nervous system was found to activate hematopoietic stem cells in the bone marrow. Recently, psychosocial stress was also convincingly linked to leukocytosis and atherosclerosis progression [13 ]. Medical residents working in the stressful environment of the ICU had higher numbers of neutrophils, monocytes and lymphocytes compared with when off duty. Mice subjected to stress displayed increased hematopoietic stem cell proliferation and increased output of neutrophils and inflammatory monocytes, and developed lesions with a vulnerable plaque phenotype. These events were linked together by increased release of noradrenaline from sympathetic nerves during stress, which signaled through the b3adrenergic receptor to decrease C-X-C motif chemokine 12 (CXCL12) production in the bone marrow, thereby elevating hematopoietic stem cell proliferation. This chain of events could be broken by administration of a b3-adrenergic receptor blocker resulting in decreased plaque inflammation. The recently re-evaluated contribution of local proliferation of macrophages and plasticity of SMCs uproot a long withstanding belief that monocytes recruited to the growing lesion are the origin of most of the foam cells. These surprising results warrant some serious rethinking of the role of monocytederived macrophage foam cells in atherosclerosis. &
&&
Acknowledgements None. Financial support and sponsorship None. Conflicts of interest None.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol 1994; 14:840–856.
68
www.co-lipidology.com
2. Chaabane C, Coen M, Bochaton-Piallat M-L. Smooth muscle cell phenotypic & switch: implications for foam cell formation. Curr Opin Lipidol 2014; 25:374– 379. Recent review summarizing the evidence for phenotypic switching of SMCs within atherosclerotic lesions. 3. Allahverdian S, Chehroudi AC, McManus BM, et al. Contribution of intimal && smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation 2014; 129:1551–1559. Shows by analyzing foam cell-rich lesions (types II and III) in human coronary arteries, from hearts explanted at the time of transplantation, with a staining method that preserves lipids that about half of the foam cells were also a-smooth muscle actin positive. Foam cells of SMC origin were found to express less ABCA1 than foam cells of myeloid origin, suggesting that reduced cholesterol trafficking could be the cause of cholesterol accumulation in foam cells of SMC origin. 4. Feil S, Fehrenbacher B, Lukowski R, et al. Transdifferentiation of vascular && smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res 2014; 115:662–667. Shows by genetic fate mapping (tamoxifen-inducible Cre expressed from the SM22a locus combined with Cre-activatable ROSA26 reporter) that medial SMCs can transdifferentiate to macrophage-like cells that have lost expression of classic SMC markers and make up a major constituent in advanced atherosclerotic lesions. The SMCs originally found in the media in young mice seem to migrate to the intima in older atherosclerotic mice where they undergo clonal expansion to form large patches of SMCs with reduced or lost a-smooth muscle actin expression but gained expression of macrophage markers and oxidized LDL staining. 5. Ubil E, Duan J, Pillai ICL, et al. Mesenchymal –endothelial transition & contributes to cardiac neovascularization. Nature 2014; 514:585– 590. Shows that fibroblasts can act as a source of endothelial cells after cardiac injury using genetic fate mapping to label cardiac fibroblasts. This cellular plasticity seems to have an important role in cardiac repair after ischemia–reperfusion injury, as disruption of mesenchymal–endothelial transition, by p53 inhibition, worsened postinfarct vascularity and cardiac function. 6. Sayed N, Wong WT, Ospino F, et al. Transdifferentiation of human fibroblasts & to endothelial cells: role of innate immunity. Circulation 2014. [Epub ahead of print]. doi: 10.1161/CIRCULATIONAHA.113.007394. Shows that Toll-like receptor 3 agonists in combination with endothelial cell growth factors can transdifferentiate human fibroblasts into endothelial cells. These endothelial cells significantly improved limb perfusion and neovascularization and reduced tissue injury when hind limb ischemia was induced in mice by ligation of the femoral artery. 7. Swirski FK, Nahrendorf M, Etzrodt M, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 2009; 325:612–616. 8. Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates atherosclerosis. Nature 2012; 487:325–329. 9. Heidt T, Courties G, Dutta P, et al. Differential contribution of monocytes to && heart macrophages in steady-state and after myocardial infarction. Circ Res 2014; 115:284–295. Shows that resident macrophages die or emigrate from the ischemic myocardium of mice and that the reduced macrophage pool is replenished by splenic monocytes. In the steady-state situation and in the chronic phase after myocardial infarction, however, local proliferation dominates and the macrophage niche in the heart is largely independent from the blood monocyte pool. 10. Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 2013; 19:1166–1172. 11. Robbins CS, Chudnovskiy A, Rauch PJ, et al. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation 2012; 125:364–374. 12. Courties G, Herisson F, Sager H, et al. Ischemic stroke activates hemato& poietic bone marrow stem cells. Circ Res 2014. [Epub ahead of print]. doi: 10.1161/CIRCRESAHA.116.305207. Shows that increased signaling of the sympathetic nervous system after a transient middle cerebral artery occlusion Toll-like receptor 3 in mice activates hematopoietic stem cells in the bone marrow, which results in increased output of neutrophils and inflammatory monocytes. In contrast to the expansion of myeloid progenitor cells, lymphoid progenitors were decreased. 13. Heidt T, Sager HB, Courties G, et al. Chronic variable stress activates && hematopoietic stem cells. Nat Med 2014; 20:754–758. Shows in mice exposed to variable and chronic stress that sympathetic nerves release more noradrenaline that signals through the b3-adrenergic receptor in the bone marrow to decrease CXCL12 production. The decreased CXCL12 production elevates hematopoietic stem cell proliferation and enhances neutrophil and monocyte production, causing increased release of inflammatory leukocytes into the circulation that promotes plaque inflammation.
Volume 26 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Bimonthly update Atherosclerosis: cell biology and lipoproteins
FURTHER RECOMMENDED READING Weirather J, Hofmann UDW, Beyersdorf N, et al. Foxp3R CD4R T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res 2014; 115:55–67. Shows that regulatory T cells beneficially influence wound healing in a mouse model of myocardial infarction (permanent left coronary artery ligation) by reducing cardiac inflammation and promoting collagen deposition. FoxP3-positive regulatory T cells were depleted by administration of diphtheria toxin to mice genetically engineered to express diphtheria toxin receptor under the control of the FoxP3 promoter. Regulatory T-cell function was boosted by administration of superagonistic CD28-specific monoclonal antibodies. Regulatory T-cell depletion or activation was associated with M1 or M2 macrophage differentiation, respectively.
&&
Patel RS, Li Q, Ghasemzadeh N, et al. Circulating CD34R progenitor cells and risk & of mortality in a population with coronary artery disease. Circ Res 2014. [Epub ahead of print]. doi: 10.1161/CIRCRESAHA.116.304187. Shows that bone marrow-derived CD34R mononuclear progenitor cells were inversely associated with risk of all-cause death in two sizeable cohorts undergoing coronary angiography. Mohanta SK, Yin C, Peng L, et al. Artery tertiary lymphoid organs contribute to & innate and adaptive immune responses in advanced mouse atherosclerosis. Circ Res 2014; 114:1772–1787. Authoritative review that summarizes our current understanding of how artery tertiary lymphoid organs are organized and compartmentalized on the cellular level. Artery tertiary lymphoid organs likely organize T-cell and B-cell autoimmune responses in advanced atherosclerosis and the authors propose that a disturbed balance between disease-promoting and disease-inhibiting immune cell subsets could trigger clinically overt atherosclerosis.
0957-9672 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-lipidology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
69
Atherosclerosis: cell biology and lipoproteins Harry Bjo¨rkbacka
The monocyte-derived macrophage foam cell has long been thought of as the archetypical cell in atherosclerotic lesions. Recent studies, however, indicate that many cells considered to be monocyte-derived macrophage foam cells have, in fact, a smooth muscle cell (SMC) origin. Other recent studies extend the concept of cellular plasticity to other vascular cells. It has long been recognized that SMCs can ingest lipids and contribute to foam cell formation in human atherosclerotic lesions [1]. SMCs undergo a phenotypic switch when they migrate from the media to the intima in atherosclerotic plaque formation, but how this process contributes to SMC foam cell formation is far from well understood, although in-vitro studies [2 ] have associated oxidized LDL-induced foam cell formation to phenotypic switching. Recently, Allahverdian et al. [3 ] found by analyzing foam cell-rich lesions in human coronary arteries from hearts explanted at the time of transplantation that as much as half of the foam cells were also a-smooth muscle actin positive. Given that large gene expression array studies have not found any evidence for a-smooth muscle actin expression in cells of the myeloid lineage and that a-smooth muscle actin staining likely underestimates the number of foam cells with SMC origin, as some intimal SMCs have been reported to express very little a-smooth muscle actin, the authors conclude that the majority of foam cells in human coronary atherosclerosis are likely SMC derived. The authors find that foam cells of SMC origin express less ATP-binding cassette transporter 1, sub-family A (ABCA1) than foam cells of myeloid origin, suggesting that reduced cholesterol trafficking could be the cause of cholesterol accumulation in foam cells of SMC origin. In support of the observational data in humans, Feil et al. [4 ] recently showed with elegant genetic fate mapping experiments in mice that medial SMCs can transdifferentiate to macrophage-like cells that make up a major constituent in advanced atherosclerotic lesions. The SMCs originally found in the media in young mice seemed to migrate to the intima in older atherosclerotic mice where they underwent clonal expansion to form large patches of SMCs with reduced or lost a-smooth muscle actin expression, while gaining expression of macrophage markers, &
&&
&&
such as CD68 and galectin-3. Interestingly, other vascular cells also display similar cellular plasticity. Ubil et al. [5 ] recently showed using genetic fate mapping in mice that fibroblast can act as a source of endothelial cells during cardiac injury and that these endothelial cells with a fibroblast origin have an important role in cardiac repair after ischemiareperfusion injury. Along the same lines, Sayed et al. [6 ] recently showed that Toll-like receptor 3 agonists in combination with endothelial cell growth factors can transdifferentiate human fibroblasts into endothelial cells that can reduce tissue injury in a mouse hind limb ischemia model. At the same time as the macrophage contribution to foam cells is put in question, the contribution of monocyte recruitment and subsequent differentiation into macrophages versus local proliferation of resident macrophages is being evaluated in cardiac ischemia and atherosclerosis. Monocytes have previously been shown [7] to make up a splenic reservoir that is quickly mobilized in response to ischemic myocardial injury. The monocyte progenitors that seed the spleen after an ischemic injury boost monocyte production that, subsequently, accelerates atherosclerosis and may explain why individuals suffering coronary events have a high risk of recurring events [8]. Recently, by putting mice in parabiosis with joint circulation, Heidt et al. [9 ] showed that monocytes replenish the dying or emigrating macrophage pool in the ischemic myocardium, whereas local proliferation of resident macrophages dominated the steady-state and chronic phase after myocardial infarction. In atherosclerotic lesions, macrophage accumulation is also dominated by local proliferation of macrophages rather than influx of monocytes; it has been shown [10,11] that monocytes undergoing extramedullary hematopoiesis in the spleen can accumulate and contribute to &
&
&&
Department of Clinical Sciences, Ska˚ne University Hospital, Lund University, Malmo¨, Sweden Correspondence to Harry Bjo¨rkbacka, Experimental Cardiovascular Research, CRC Lund University, Building 91:12, Jan Waldenstro¨ms gata 35, Malmo¨ University Hospital, SE-205 02 Malmo¨, Sweden. Tel: +46 0 40 391205; fax: +46 0 40 391212; e-mail: [email protected] Curr Opin Lipidol 2015, 26:67–69 DOI:10.1097/MOL.0000000000000150
0957-9672 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-lipidology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Bimonthly update Atherosclerosis: cell biology and lipoproteins
atherosclerotic lesion progression. Lately, Courties et al. [12 ] showed that ischemic stroke in mice activates hematopoietic stem cells leading to increased numbers of circulating myeloid cells, similar to what is often observed in stroke patients. Interestingly, increased signaling of the sympathetic nervous system was found to activate hematopoietic stem cells in the bone marrow. Recently, psychosocial stress was also convincingly linked to leukocytosis and atherosclerosis progression [13 ]. Medical residents working in the stressful environment of the ICU had higher numbers of neutrophils, monocytes and lymphocytes compared with when off duty. Mice subjected to stress displayed increased hematopoietic stem cell proliferation and increased output of neutrophils and inflammatory monocytes, and developed lesions with a vulnerable plaque phenotype. These events were linked together by increased release of noradrenaline from sympathetic nerves during stress, which signaled through the b3adrenergic receptor to decrease C-X-C motif chemokine 12 (CXCL12) production in the bone marrow, thereby elevating hematopoietic stem cell proliferation. This chain of events could be broken by administration of a b3-adrenergic receptor blocker resulting in decreased plaque inflammation. The recently re-evaluated contribution of local proliferation of macrophages and plasticity of SMCs uproot a long withstanding belief that monocytes recruited to the growing lesion are the origin of most of the foam cells. These surprising results warrant some serious rethinking of the role of monocytederived macrophage foam cells in atherosclerosis. &
&&
Acknowledgements None. Financial support and sponsorship None. Conflicts of interest None.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol 1994; 14:840–856.
68
www.co-lipidology.com
2. Chaabane C, Coen M, Bochaton-Piallat M-L. Smooth muscle cell phenotypic & switch: implications for foam cell formation. Curr Opin Lipidol 2014; 25:374– 379. Recent review summarizing the evidence for phenotypic switching of SMCs within atherosclerotic lesions. 3. Allahverdian S, Chehroudi AC, McManus BM, et al. Contribution of intimal && smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation 2014; 129:1551–1559. Shows by analyzing foam cell-rich lesions (types II and III) in human coronary arteries, from hearts explanted at the time of transplantation, with a staining method that preserves lipids that about half of the foam cells were also a-smooth muscle actin positive. Foam cells of SMC origin were found to express less ABCA1 than foam cells of myeloid origin, suggesting that reduced cholesterol trafficking could be the cause of cholesterol accumulation in foam cells of SMC origin. 4. Feil S, Fehrenbacher B, Lukowski R, et al. Transdifferentiation of vascular && smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res 2014; 115:662–667. Shows by genetic fate mapping (tamoxifen-inducible Cre expressed from the SM22a locus combined with Cre-activatable ROSA26 reporter) that medial SMCs can transdifferentiate to macrophage-like cells that have lost expression of classic SMC markers and make up a major constituent in advanced atherosclerotic lesions. The SMCs originally found in the media in young mice seem to migrate to the intima in older atherosclerotic mice where they undergo clonal expansion to form large patches of SMCs with reduced or lost a-smooth muscle actin expression but gained expression of macrophage markers and oxidized LDL staining. 5. Ubil E, Duan J, Pillai ICL, et al. Mesenchymal –endothelial transition & contributes to cardiac neovascularization. Nature 2014; 514:585– 590. Shows that fibroblasts can act as a source of endothelial cells after cardiac injury using genetic fate mapping to label cardiac fibroblasts. This cellular plasticity seems to have an important role in cardiac repair after ischemia–reperfusion injury, as disruption of mesenchymal–endothelial transition, by p53 inhibition, worsened postinfarct vascularity and cardiac function. 6. Sayed N, Wong WT, Ospino F, et al. Transdifferentiation of human fibroblasts & to endothelial cells: role of innate immunity. Circulation 2014. [Epub ahead of print]. doi: 10.1161/CIRCULATIONAHA.113.007394. Shows that Toll-like receptor 3 agonists in combination with endothelial cell growth factors can transdifferentiate human fibroblasts into endothelial cells. These endothelial cells significantly improved limb perfusion and neovascularization and reduced tissue injury when hind limb ischemia was induced in mice by ligation of the femoral artery. 7. Swirski FK, Nahrendorf M, Etzrodt M, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 2009; 325:612–616. 8. Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates atherosclerosis. Nature 2012; 487:325–329. 9. Heidt T, Courties G, Dutta P, et al. Differential contribution of monocytes to && heart macrophages in steady-state and after myocardial infarction. Circ Res 2014; 115:284–295. Shows that resident macrophages die or emigrate from the ischemic myocardium of mice and that the reduced macrophage pool is replenished by splenic monocytes. In the steady-state situation and in the chronic phase after myocardial infarction, however, local proliferation dominates and the macrophage niche in the heart is largely independent from the blood monocyte pool. 10. Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 2013; 19:1166–1172. 11. Robbins CS, Chudnovskiy A, Rauch PJ, et al. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation 2012; 125:364–374. 12. Courties G, Herisson F, Sager H, et al. Ischemic stroke activates hemato& poietic bone marrow stem cells. Circ Res 2014. [Epub ahead of print]. doi: 10.1161/CIRCRESAHA.116.305207. Shows that increased signaling of the sympathetic nervous system after a transient middle cerebral artery occlusion Toll-like receptor 3 in mice activates hematopoietic stem cells in the bone marrow, which results in increased output of neutrophils and inflammatory monocytes. In contrast to the expansion of myeloid progenitor cells, lymphoid progenitors were decreased. 13. Heidt T, Sager HB, Courties G, et al. Chronic variable stress activates && hematopoietic stem cells. Nat Med 2014; 20:754–758. Shows in mice exposed to variable and chronic stress that sympathetic nerves release more noradrenaline that signals through the b3-adrenergic receptor in the bone marrow to decrease CXCL12 production. The decreased CXCL12 production elevates hematopoietic stem cell proliferation and enhances neutrophil and monocyte production, causing increased release of inflammatory leukocytes into the circulation that promotes plaque inflammation.
Volume 26 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Bimonthly update Atherosclerosis: cell biology and lipoproteins
FURTHER RECOMMENDED READING Weirather J, Hofmann UDW, Beyersdorf N, et al. Foxp3R CD4R T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res 2014; 115:55–67. Shows that regulatory T cells beneficially influence wound healing in a mouse model of myocardial infarction (permanent left coronary artery ligation) by reducing cardiac inflammation and promoting collagen deposition. FoxP3-positive regulatory T cells were depleted by administration of diphtheria toxin to mice genetically engineered to express diphtheria toxin receptor under the control of the FoxP3 promoter. Regulatory T-cell function was boosted by administration of superagonistic CD28-specific monoclonal antibodies. Regulatory T-cell depletion or activation was associated with M1 or M2 macrophage differentiation, respectively.
&&
Patel RS, Li Q, Ghasemzadeh N, et al. Circulating CD34R progenitor cells and risk & of mortality in a population with coronary artery disease. Circ Res 2014. [Epub ahead of print]. doi: 10.1161/CIRCRESAHA.116.304187. Shows that bone marrow-derived CD34R mononuclear progenitor cells were inversely associated with risk of all-cause death in two sizeable cohorts undergoing coronary angiography. Mohanta SK, Yin C, Peng L, et al. Artery tertiary lymphoid organs contribute to & innate and adaptive immune responses in advanced mouse atherosclerosis. Circ Res 2014; 114:1772–1787. Authoritative review that summarizes our current understanding of how artery tertiary lymphoid organs are organized and compartmentalized on the cellular level. Artery tertiary lymphoid organs likely organize T-cell and B-cell autoimmune responses in advanced atherosclerosis and the authors propose that a disturbed balance between disease-promoting and disease-inhibiting immune cell subsets could trigger clinically overt atherosclerosis.
0957-9672 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-lipidology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
69
