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RGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling.

Patel J, McNeill E, Douglas G, Hale AB, de Bono J, Lee R, Iqbal AJ, Regan-Komito D, Stylianou E, Greaves DR, Channon KM - Nat Commun (2015)

Bottom Line: Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation.Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling.Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

ABSTRACT
Chemokine signalling drives monocyte recruitment in atherosclerosis and aortic aneurysms. The mechanisms that lead to retention and accumulation of macrophages in the vascular wall remain unclear. Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation. Here we show that Rgs1 is upregulated in atherosclerotic plaque and aortic aneurysms. Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling. In early atherosclerotic lesions, Rgs1 regulates macrophage accumulation and is required for the formation and rupture of Angiotensin II-induced aortic aneurysms, through effects on leukocyte retention. Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease.

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Related in: MedlinePlus

Schematic outline of the regulation of RGS1 in monocyte–macrophages.The expression of Rgs1 in non-activated circulating monocytes is low and upregulated with monocyte activation by pro-inflammatory stimuli during the recruitment phase. Monocytes differentiate into inflammatory macrophages, whereupon they increase their expression of Rgs1, when they are required to generate an inflammatory response. RGS1 terminates chemokine signalling and thereby reduces the capacity for cell migration, which results in the accumulation of macrophages in the subintimal space. RGS1 might be overactivated in the local environment and perpetuate inflammation in the vessel wall. Thus, the differential expression of Rgs1 in monocytes and macrophages may affect early atherosclerotic lesion and aortic aneurysm progression in vivo. This may also be applicable in other inflammatory diseases where dysregulation of monocyte–macrophage trafficking can influence the result of an inflammatory response.
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f7: Schematic outline of the regulation of RGS1 in monocyte–macrophages.The expression of Rgs1 in non-activated circulating monocytes is low and upregulated with monocyte activation by pro-inflammatory stimuli during the recruitment phase. Monocytes differentiate into inflammatory macrophages, whereupon they increase their expression of Rgs1, when they are required to generate an inflammatory response. RGS1 terminates chemokine signalling and thereby reduces the capacity for cell migration, which results in the accumulation of macrophages in the subintimal space. RGS1 might be overactivated in the local environment and perpetuate inflammation in the vessel wall. Thus, the differential expression of Rgs1 in monocytes and macrophages may affect early atherosclerotic lesion and aortic aneurysm progression in vivo. This may also be applicable in other inflammatory diseases where dysregulation of monocyte–macrophage trafficking can influence the result of an inflammatory response.

Mentions: For the first time, we provide new evidence for a role for RGS1, a downstream mediator of GPCR signalling, in the recruitment and accumulation of leukocytes to the aorta during vascular inflammation in atherosclerosis, aortic aneurysm formation and aneurysm rupture. The major findings of this study are, first, that Rgs1 is upregulated in atherosclerotic vessels and in AAA, is low in circulating monocytes but is greatly upregulated in response to activation and macrophage differentiation (Fig. 7); second, that Rgs1 deficiency increases macrophage chemotaxis and reduces chemokine receptor homologous desensitization; and third, Rgs1 deficiency protects against early atherosclerotic plaque and aortic aneurysm rupture in ApoE−/− mice, due to reduced accumulation of leukocytes in the artery wall. Thus, RGS1 contributes to the persistence of macrophages in the initial stages of atherosclerosis and promotes aortic aneurysm formation and rupture.


RGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling.

Patel J, McNeill E, Douglas G, Hale AB, de Bono J, Lee R, Iqbal AJ, Regan-Komito D, Stylianou E, Greaves DR, Channon KM - Nat Commun (2015)

Schematic outline of the regulation of RGS1 in monocyte–macrophages.The expression of Rgs1 in non-activated circulating monocytes is low and upregulated with monocyte activation by pro-inflammatory stimuli during the recruitment phase. Monocytes differentiate into inflammatory macrophages, whereupon they increase their expression of Rgs1, when they are required to generate an inflammatory response. RGS1 terminates chemokine signalling and thereby reduces the capacity for cell migration, which results in the accumulation of macrophages in the subintimal space. RGS1 might be overactivated in the local environment and perpetuate inflammation in the vessel wall. Thus, the differential expression of Rgs1 in monocytes and macrophages may affect early atherosclerotic lesion and aortic aneurysm progression in vivo. This may also be applicable in other inflammatory diseases where dysregulation of monocyte–macrophage trafficking can influence the result of an inflammatory response.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374153&req=5

f7: Schematic outline of the regulation of RGS1 in monocyte–macrophages.The expression of Rgs1 in non-activated circulating monocytes is low and upregulated with monocyte activation by pro-inflammatory stimuli during the recruitment phase. Monocytes differentiate into inflammatory macrophages, whereupon they increase their expression of Rgs1, when they are required to generate an inflammatory response. RGS1 terminates chemokine signalling and thereby reduces the capacity for cell migration, which results in the accumulation of macrophages in the subintimal space. RGS1 might be overactivated in the local environment and perpetuate inflammation in the vessel wall. Thus, the differential expression of Rgs1 in monocytes and macrophages may affect early atherosclerotic lesion and aortic aneurysm progression in vivo. This may also be applicable in other inflammatory diseases where dysregulation of monocyte–macrophage trafficking can influence the result of an inflammatory response.
Mentions: For the first time, we provide new evidence for a role for RGS1, a downstream mediator of GPCR signalling, in the recruitment and accumulation of leukocytes to the aorta during vascular inflammation in atherosclerosis, aortic aneurysm formation and aneurysm rupture. The major findings of this study are, first, that Rgs1 is upregulated in atherosclerotic vessels and in AAA, is low in circulating monocytes but is greatly upregulated in response to activation and macrophage differentiation (Fig. 7); second, that Rgs1 deficiency increases macrophage chemotaxis and reduces chemokine receptor homologous desensitization; and third, Rgs1 deficiency protects against early atherosclerotic plaque and aortic aneurysm rupture in ApoE−/− mice, due to reduced accumulation of leukocytes in the artery wall. Thus, RGS1 contributes to the persistence of macrophages in the initial stages of atherosclerosis and promotes aortic aneurysm formation and rupture.

Bottom Line: Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation.Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling.Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

ABSTRACT
Chemokine signalling drives monocyte recruitment in atherosclerosis and aortic aneurysms. The mechanisms that lead to retention and accumulation of macrophages in the vascular wall remain unclear. Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation. Here we show that Rgs1 is upregulated in atherosclerotic plaque and aortic aneurysms. Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling. In early atherosclerotic lesions, Rgs1 regulates macrophage accumulation and is required for the formation and rupture of Angiotensin II-induced aortic aneurysms, through effects on leukocyte retention. Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease.

Show MeSH
Related in: MedlinePlus