Association of CD11b<sup>+</sup>Monocytes and Anti–Vascular Endothelial Growth Factor Injections in Treatment of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Subhi, Yousif; Nielsen, Marie Krogh; Molbech, Christopher Rue; Falk, Mads Krüger; Singh, Amardeep; Hviid, Thomas Vauvert F.; Nissen, Mogens Holst; Sørensen, Torben Lykke

doi:10.1001/jamaophthalmol.2019.0010

Cited by 26 publications

(20 citation statements)

References 41 publications

(100 reference statements)

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“…Taken together, these findings are suggestive of a local degradation and matrix remodeling, and our findings in this study suggest that such activity, at least in Caucasian patients, are not present on a systemic level. The reason to why immune cells infiltrates and secretes MMP-9 remain incompletely understood, but it appears that changes or potential dysfunction in the circulating immune cells may be one contributing factor of disease etiology [ 24 , 25 , 26 , 27 , 28 , 29 ]. However, at this point, very few etiological studies are published and further studies are warranted to better understand the etiological mechanisms of PCV.…”

Section: Discussionmentioning

confidence: 99%

Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy

Sørensen

Subhi

Molbech

et al. 2020

Vision

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Background: Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) are regulating enzymes of the extracellular matrix. A systemic imbalance of MMP-9 and TIMP-1, thought to reflect an imbalance of the extracellular matrix homeostasis, is previously associated with polypoidal choroidal vasculopathy (PCV) in Asian patients. Previous studies suggest inter-ethnical differences in the genetic background and etiology of PCV. To further explore this issue, we studied the plasma levels of MMP-9 and TIMP-1 in Caucasian patients with PCV and compared to healthy age-matched controls. Methods: For this prospective case-control study, 60 participants were recruited who were either patients with PCV (n = 26) or healthy controls (n = 34). All participants underwent detailed clinical examination. We sampled fresh venous blood, isolated plasma, and quantified plasma concentrations of the extracellular matrix regulators MMP-9 and TIMP-1 using electrochemiluminescence immunoassays. Results: Plasma levels of MMP-9 (p = 0.4), TIMP-1 (p = 0.9), and MMP-9/TIMP-1 ratio (p = 0.4) did not differ significantly between patients with PCV and healthy controls. No differences appeared after adjusting for influencing co-variates in multivariate analyses. Conclusion: We demonstrate that Caucasian patients with PCV do not have altered levels of plasma MMP-9 or plasma TIMP-1. These findings suggest no strong evidence of a systemic imbalance of the extracellular matrix homeostasis in Caucasian patients with PCV. Our findings are in line with studies of other aspects of PCV that are also subject to significant inter-ethnical differences.

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Section: Discussionmentioning

confidence: 99%

Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy

Sørensen

Subhi

Molbech

et al. 2020

Vision

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“…There is evidence to suggest that the MCP‐1 receptor CCR2 expressed on circulating monocytes may play a role in PCV (Subhi et al. , 2019a), whereas the role of the IP‐10 receptor CXCR3 is more unclear and so far only reported in relation to T‐helper cells (Subhi et al. 2019b).…”

Section: Discussionmentioning

confidence: 99%

Plasma levels of inflammatory chemokines in patients with polypoidal choroidal vasculopathy

Sørensen

Subhi

Molbech

et al. 2019

Acta Ophthalmologica

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Purpose: Chemokines are a group of cytokines that guide immune cell migration. We studied plasma levels of inflammatory chemokines in patients with polypoidal choroidal vasculopathy (PCV) and compared with healthy agematched control individuals. Methods: This was a clinic-based prospective case-control study of participants (n = 60) with either PCV (n = 26) or age-matched healthy controls (n = 34). We sampled fresh venous blood and isolated plasma for analysis. We used U-PLEX Human Assays to quantify concentrations of the inflammatory chemokines MCP-1/CCL2, RANTES/CCL5, eotaxin/CCL11, IP-10/CXCL10 and fractalkine/CX3CL1. Results: Plasma levels of fractalkine was significantly higher in patients with PCV when compared to healthy controls (mean AE SD: 7291 AE 2461 pg/ml versus 5879 AE 2001 pg/ml; p = 0.021). Plasma levels of MCP-1 (p = 0.846), RANTES (p = 0.288), eotaxin (p = 0.496) and IP-10 (p = 0.352) did not differ significantly between the groups. To evaluate possible biomarker quality of fractalkine, we used a ROC analysis and found a positive but weak discriminatory ability (AUC = 0.68). Conclusion: Patients with PCV have a higher plasma level of fractalkine. Although the differences do not possess strong biomarker qualities, they inform on disease processes of a poorly understood disease and suggest that the fractalkine-CX3CR1 axis may be involved. As this study did not investigate local chemokine concentrations, we are unable to confirm or disprove any local chorioretinal interaction, and our findings should be interpreted with such caution.

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“…Exactly how inflammation leads to macular damage in AMD remains poorly defined. Increased systemic and local inflammatory responses, including complement activation [11][12][13][14][15], immune cell alteration [16][17][18][19] and cytokine production [20][21][22][23][24] have been observed in AMD. Previously, we and others have reported increased circulating neutrophils in nAMD patients [19,25,26].…”

Section: Introductionmentioning

confidence: 99%

Plasma level of lipocalin 2 is increased in neovascular age-related macular degeneration patients, particularly those with macular fibrosis

et al. 2020

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Background Previously, we and others have reported higher populations of circulating neutrophils in patients with neovascular age-related macular degeneration (nAMD). Neutrophil gelatinase-associated lipocalin (NGAL, also known as lipocalin-2, LCN2), an important innate immune mediator, is known to be critically involved in sterile inflammation-mediated organ failure, fibrosis, cancer progression and retinal degeneration. This study investigated the plasma levels of LCN2, matrix metalloproteinase 9 (MMP9) and LCN2/MMP9 complex in different types of nAMD and examined whether the levels were related to patients’ responsiveness to anti-VEGF therapy. Results One hundred and seventy-four nAMD patients, including 108 with choroidal neovascularisation (CNV), 32 with retinal angiomatous proliferation (RAP), 23 with polypoidal choroidal vasculopathy (PCV) and 11 unclassified patients, and 43 healthy controls were recruited to this case-control study. Fifty-eight nAMD patients had macular fibrosis and 110 patients did not. Out of the 174 nAMD patients, 80 patients responded completely, 90 responded partially, and 4 did not respond to the anti-VEGF therapy. The plasma levels of LCN2 in nAMD patients (181.46 ± 73.62 ng/ml) was significantly higher than that in healthy controls (152.24 ± 49.55 ng/ml, P = 0.047). However, the difference disappeared after adjusting for age. A positive correlation between plasma level of LCN2 and age was observed in nAMD patients (r = 0.29, P = 0.0002) but not in healthy controls. The plasma level of LCN2 was also positively correlated with circulating neutrophils in nAMD patients (r = 0.34, p = 0.0007) but not in healthy controls (r = 0.057, p = 0.77). No correlation was observed between age and circulating neutrophils. Further analysis of nAMD subtypes uncovered a significantly higher level of LCN2 in patients with macular fibrosis even after adjusting for age. No relationship was observed between plasma levels of LCN2 and patients’ responsiveness to anti-VEGF therapy. The plasma levels of MMP9 and LCN2/MMP9 complex were comparable between nAMD and controls. Conclusions Our results suggest that higher plasma levels of LCN2 in nAMD are related to ageing and increased population of circulating neutrophils. Our results also suggest that higher levels of LCN2 may increase the risk of macular fibrosis in nAMD.

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Association of CD11b⁺Monocytes and Anti–Vascular Endothelial Growth Factor Injections in Treatment of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Cited by 26 publications

References 41 publications

Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy

Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy

Plasma levels of inflammatory chemokines in patients with polypoidal choroidal vasculopathy

Plasma level of lipocalin 2 is increased in neovascular age-related macular degeneration patients, particularly those with macular fibrosis

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Association of CD11b+Monocytes and Anti–Vascular Endothelial Growth Factor Injections in Treatment of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Cited by 26 publications

References 41 publications

Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy

Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy

Plasma levels of inflammatory chemokines in patients with polypoidal choroidal vasculopathy

Plasma level of lipocalin 2 is increased in neovascular age-related macular degeneration patients, particularly those with macular fibrosis

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Association of CD11b⁺Monocytes and Anti–Vascular Endothelial Growth Factor Injections in Treatment of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy