CXCR7 suppression modulates macrophage phenotype and function to ameliorate post-myocardial infarction injury

Zhang, Junshi; Zhang, Ying; Xin, Shifeng; Wu, Michael; Zhang, Yaling; Sun, Lihua

doi:10.1007/s00011-020-01335-z

Cited by 13 publications

(10 citation statements)

References 31 publications

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“…The functional role of ACKR3 in cell adhesion has been confirmed in different cell lines [ 11 , 28 , 37 , 56 , 68 ] and it points towards an inflammatory role of this receptor, as also implicated by other studies [ 41 , 64 ]. ACKR3 was shown to be vital for very late antigen-4 (VLA-4) and lymphocyte function-associated antigen-1 (LFA-1)-driven adhesion of human lymphocytes onto inflamed endothelium [ 26 ].…”

Section: Discussionsupporting

confidence: 61%

Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium

et al. 2022

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Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow room for a large residual risk; therefore, novel therapeutic candidates targeting inflammation are needed. The endothelium is the starting point of vascular inflammation underlying atherosclerosis and we could previously demonstrate that the chemokine axis CXCL12–CXCR4 plays an important role in disease development. However, the role of ACKR3, the alternative and higher affinity receptor for CXCL12 remained to be elucidated. We studied the role of arterial ACKR3 in atherosclerosis using western diet-fed Apoe−/− mice lacking Ackr3 in arterial endothelial as well as smooth muscle cells. We show for the first time that arterial endothelial deficiency of ACKR3 attenuates atherosclerosis as a result of diminished arterial adhesion as well as invasion of immune cells. ACKR3 silencing in inflamed human coronary artery endothelial cells decreased adhesion molecule expression, establishing an initial human validation of ACKR3’s role in endothelial adhesion. Concomitantly, ACKR3 silencing downregulated key mediators in the MAPK pathway, such as ERK1/2, as well as the phosphorylation of the NF-kB p65 subunit. Endothelial cells in atherosclerotic lesions also revealed decreased phospho-NF-kB p65 expression in ACKR3-deficient mice. Lack of smooth muscle cell-specific as well as hematopoietic ACKR3 did not impact atherosclerosis in mice. Collectively, our findings indicate that arterial endothelial ACKR3 fuels atherosclerosis by mediating endothelium-immune cell adhesion, most likely through inflammatory MAPK and NF-kB pathways.

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Section: Discussionsupporting

confidence: 61%

Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium

et al. 2022

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“…ACKR3 is expressed in inflammatory cells ( 103 ) and its expression is especially correlated with monocyte to macrophage differentiation ( 73 ), the degree of maturation of B cells ( 76 ) or that of dendritic cells ( 77 ). ACKR3 expression in macrophages is upregulated during polarization in vitro and following MI with positive correlation with M1 but not M2 ( 70 , 73 ) like macrophage markers. In these macrophages, ACKR3 controls CXCL12 and CXCL11-mediated chemotaxis as well as the production of pro-inflammatory cytokines such as IL-1 and Il-6 after MI indicating a deleterious role of ACKR3 in macrophages in this setting.…”

Section: Ackr3 In Cardiovascular Diseasesmentioning

confidence: 96%

“…In these macrophages, ACKR3 controls CXCL12 and CXCL11-mediated chemotaxis as well as the production of pro-inflammatory cytokines such as IL-1 and Il-6 after MI indicating a deleterious role of ACKR3 in macrophages in this setting. Invalidation of Ackr3 by shRNA before induction of MI inhibited macrophage polarization, chemotaxis and inflammation and reduced infarct size leading to an improvement of cardiac function post-MI ( 70 ). Unfortunately, the role of ACKR3 in different immune cell sub-populations in post-MI cardiac remodeling are incomplete.…”

Section: Ackr3 In Cardiovascular Diseasesmentioning

confidence: 99%

Emerging Roles of the Atypical Chemokine Receptor 3 (ACKR3) in Cardiovascular Diseases

et al. 2022

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Chemokines, and their receptors play a crucial role in the pathophysiology of cardiovascular diseases (CVD). Chemokines classically mediate their effects by binding to G-protein-coupled receptors. The discovery that chemokines can also bind to atypical chemokine receptors (ACKRs) and initiate alternative signaling pathways has changed the paradigm regarding chemokine-related functions. Among these ACKRs, several studies have highlighted the exclusive role of ACKR3, previously known as C-X-C chemokine receptor type 7 (CXCR7), in CVD. Indeed, ACKR3 exert atheroprotective, cardioprotective and anti-thrombotic effects through a wide range of cells including endothelial cells, platelets, inflammatory cells, fibroblasts, vascular smooth muscle cells and cardiomyocytes. ACKR3 functions as a scavenger receptor notably for the pleiotropic chemokine CXCL12, but also as a activator of different pathways such as β-arrestin-mediated signaling or modulator of CXCR4 signaling through the formation of ACKR3-CXCR4 heterodimers. Hence, a better understanding of the precise roles of ACKR3 may pave the way towards the development of novel and improved therapeutic strategies for CVD. Here, we summarize the structural determinant characteristic of ACKR3, the molecules targeting this receptor and signaling pathways modulated by ACKR3. Finally, we present and discuss recent findings regarding the role of ACKR3 in CVD.

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“…Moreover, targeting inflammatory cytokines and chemokines, such as IL-1, IL-6, CCL2, TGF-β, TNF-α, could be helpful in heart failure treatment [ 154 , 155 ]. For instance, suppression of chemokine receptor CXCR7 inhibits M1 macrophage polarization, chemotaxis, and inflammation to improve post-MI injury [ 156 ]. Therefore, macrophages have a therapeutic potential, and a thorough understanding of their role in the progression of heart failure is crucial.…”

Section: Conclusion and Future Aspectsmentioning

confidence: 99%

Multiple roles of cardiac macrophages in heart homeostasis and failure

2021

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Macrophages are essential components of the immune system and play a role in the normal functioning of the cardiovascular system. Depending on their origin and phenotype, cardiac macrophages perform various functions. In a steady-state, these cells play a beneficial role in maintaining cardiac homeostasis by defending the body from pathogens and eliminating apoptotic cells, participating in electrical conduction, vessel patrolling, and arterial tone regulation. However, macrophages also take part in adverse cardiac remodeling that could lead to the development and progression of heart failure (HF) in such HF comorbidities as hypertension, obesity, diabetes, and myocardial infarction. Nevertheless, studies on detailed mechanisms of cardiac macrophage function are still in progress, and could enable potential therapeutic applications of these cells. This review aims to present the latest reports on the origin, heterogeneity, and functions of cardiac macrophages in the healthy heart and in cardiovascular diseases leading to HF. The potential therapeutic use of macrophages is also briefly discussed.

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CXCR7 suppression modulates macrophage phenotype and function to ameliorate post-myocardial infarction injury

Cited by 13 publications

References 31 publications

Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium

Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium

Emerging Roles of the Atypical Chemokine Receptor 3 (ACKR3) in Cardiovascular Diseases

Multiple roles of cardiac macrophages in heart homeostasis and failure

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