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Graefe's Archive for Clinical and Experimental Ophthalmology

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Open Access 01-05-2018 | Basic Science

Inhibition of integrin α5β1 ameliorates VEGF-induced retinal neovascularization and leakage by suppressing NLRP3 inflammasome signaling in a mouse model

Authors: Ailing Sui, Yisheng Zhong, Anna M. Demetriades, Qing Lu, Yujuan Cai, Yushuo Gao, Yanji Zhu, Xi Shen, Bing Xie

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 5/2018

Abstract

Purpose

To assess the effect of inhibiting integrin α5β1 by ATN-161 on vascular endothelial growth factor (VEGF)-induced neovascularization (NV) and leakage causing retinal detachment in adult Tet/opsin/VEGF transgenic mice, and characterize the underlying mechanism of its function.

Method

Retinas from adult Tet/opsin/VEGF transgenic mice and human retinal endothelial cells (HRECs) exposed to VEGF (treated with ATN-161 or PBS) were used to carry out immunofluorescence, RT-PCR and western blot to examine expression levels of integrin α5β1 and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome. Retinal frozen section analysis was used to assess NV and leakage causing retinal detachment.

Results

In comparison to normal-treated mice, doxycycline-treated Tet/opsin/VEGF transgenic mice showed severe retinal detachment and higher integrin α5β1 expression. Furthermore, the retinal detachment was inhibited significantly by ATN-161. Additionally, ATN-161 treatment was associated with a conspicuous reduction in NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1, and mature interleukin-1β expression levels in the retinas of Tet/opsin/VEGF transgenic mice treated with doxycycline as well as in HRECs exposed to VEGF.

Conclusion

ATN-161, an antagonist of integrin α5β1, is a promising treatment for retinal neovascularization (RNV), and its retinal protection role appears to take effect through inhibition of NLRP3 inflammasome activity.

Penn JS, Rajaratnam VS, Collier RJ et al (2001) The effect of an angiostatic steroid on neovascularization in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 42:283–290PubMed

Cai Y, Tan W, Shen X et al (2016) Neutralization of IL-23 depresses experimental ocular neovascularization. Exp Eye Res 146:242–251. https://doi.org/10.1016/j.exer.2016.02.008 CrossRefPubMed

Al-Shabrawey M, Elsherbiny M, Nussbaum J et al (2013) Targeting neovascularization in ischemic retinopathy: recent advances. Expert Rev Ophthalmol 8:267–286. https://doi.org/10.1586/eop.13.17 CrossRefPubMedPubMedCentral

Fassnacht-Riederle H, Becker M, Graf N et al (2014) Effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD. Graefes Arch Clin Exp Ophthalmol 252:1705–1709. https://doi.org/10.1007/s00417-014-2589-3 CrossRefPubMedPubMedCentral

Rabinowitz R, Priel A, Rosner M et al (2012) Avastin treatment reduces retinal neovascularization in a mouse model of retinopathy of prematurity. Curr Eye Res 37:624–629. https://doi.org/10.3109/02713683.2012.669003 CrossRefPubMed

Jardeleza MSR, Miller JW (2009) Review of anti-VEGF therapy in proliferative diabetic retinopathy. Semin Ophthalmol 24:87–92. https://doi.org/10.1080/08820530902800330 CrossRefPubMed

Finger RP, Wickremasinghe SS, Baird PN et al (2014) Predictors of anti-VEGF treatment response in neovascular age-related macular degeneration. Surv Ophthalmol 59:1–18. https://doi.org/10.1016/j.survophthal.2013.03.009 CrossRefPubMed

Sørensen BH, Rasmussen LJH, Broberg BS et al (2015) Integrin β1, osmosensing, and chemoresistance in mouse ehrlich carcinoma cells. Cell Physiol Biochem 36:111–132. https://doi.org/10.1159/000374057 CrossRefPubMed

Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687. https://doi.org/10.1016/S0092-8674(02)00971-6 CrossRefPubMed

10.

Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119:3901–3903. https://doi.org/10.1242/jcs.03098 CrossRefPubMedPubMedCentral

11.

Kim S, Bell K, Mousa SA et al (2000) Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 156:1345–1362. https://doi.org/10.1016/S0002-9440(10)65005-5 CrossRefPubMedPubMedCentral

12.

Okamoto N, Tobe T, Hackett SF et al (1997) Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 151:281–291PubMedPubMedCentral

13.

Wang W, Wang F, Lu F et al (2011) The antiangiogenic effects of integrin α5β1 inhibitor (ATN-161) in vitro and in vivo. Invest Ophthalmol Vis Sci 52:7213–7220. https://doi.org/10.1167/iovs.10-7097 CrossRefPubMed

14.

Blomgran R, Brodin VP, Verma D et al (2012) Common genetic variations in the NALP3 inflammasome are associated with delayed apoptosis of human neutrophils. PLoS One 7. https://doi.org/10.1371/journal.pone.0031326

15.

Willingham WB, Allen IC, Bergstralh DT et al (2009) NLRP3 (NALP3, cryopyrin) facilitates in vivo caspase-1, necrosis, and HMGB1 release via inflammasome-dependent and-independent pathways. J Immunol 183:2008–2015. https://doi.org/10.4049/jimmunol.0900138 CrossRefPubMedPubMedCentral

16.

Agostini L, Martinon F, Burns K et al (2004) Tschopp, NALP3 forms an IL-1β-processing inflammasome with increased activity in muckle-wells autoinflammatory disorder. Immunity 20:319–325. https://doi.org/10.1016/S1074-7613(04)00046-9 CrossRefPubMed

17.

Dvoriantchikova G, Barakat DJ, Hernandez E et al (2010) Toll-like receptor 4 contributes to retinal ischemia/reperfusion injury. Mol Vis 16:1907–1912PubMedPubMedCentral

18.

Chi W, Li F, Chen H et al (2014) Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1 production in acute glaucoma. Proc Natl Acad Sci 111:11181–11186. https://doi.org/10.1073/pnas.1402819111 CrossRefPubMedPubMedCentral

19.

Okamoto N, Gehlbach P, Duh EJ et al (2002) Inducible expression of vascular endothelial growth factor in adult mice causes severe proliferative retinopathy and retinal detachment. Am J Pathol 160:711–719CrossRefPubMedPubMedCentral

20.

Nambu H, Nambu R, Oshima Y et al (2004) Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood-retinal barrier. Gene Ther 11:865–873. https://doi.org/10.1038/sj.gt.3302230 CrossRefPubMed

21.

Yurdagul A, Green J, Albert P et al (2014) α5β1 integrin signaling mediates oxidized low-density lipoprotein-induced inflammation and early atherosclerosis. Arterioscler Thromb Vasc Biol 34:1362–1373. https://doi.org/10.1161/ATVBAHA.114.303863 CrossRefPubMedPubMedCentral

22.

Tian Z, Liu Y, Yang B et al (2017) Astagalus polysaccharide attenuates murine colitis through inhibiton of the NLRP3 inflammasome. Planta Med 83:70–77. https://doi.org/10.1055/s-0042-108589 PubMed

23.

Zhu Y, Tan W, Demetriades AM et al (2015) IL-17A neutralization alleviated ocular neovascularization by promoting M2 and mitigating M1 macrophage polarization. Immunology 147:414–428. https://doi.org/10.1111/imm.12571 CrossRef

24.

Asmussen A, Fink K, Busch HJ et al (2016) Inflammasome and toll-like receptor signaling in human monocytes after successful cardiopulmonary resuscitation. Crit Care 20:170. https://doi.org/10.1186/s13054-016-1340-3 CrossRefPubMedPubMedCentral

25.

Zhao D, Wu Y, Zhuang J et al (2014) Activation of NLRP1 and NLRP3 inflammasomes contributed to cyclic stretch-induced pyroptosis and release of IL-1β in human periodontal ligament cells. Oncotarget (7):68292–68302. https://doi.org/10.18632/oncotarget.11944

26.

Miki K, Miki A, Matsuoka M et al (2009) Effects of intraocular ranibizumab and bevacizumab in transgenic mice expressing human vascular endothelial growth factor. Ophthalmology 116:1748–1754. https://doi.org/10.1016/j.ophtha.2009.05.020.Effects CrossRefPubMedPubMedCentral

27.

Rofagha S, Bhisitkul RB, Boyer DS et al (2013) Seven-year outcomes in ranibizumab-treated patients in anchor, marina, and horizon: a multicenter cohort study (SEVEN-UP). Ophthalmology 120:2292–2299. https://doi.org/10.1016/j.ophtha.2013.03.046 CrossRefPubMed

28.

Arnaout MA, Mahalingam B, Xiong JP (2005) Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 21:381–410. https://doi.org/10.1146/annurev.cellbio.21.090704.151217 CrossRefPubMed

29.

Jun HK, Lee SH, Lee HR et al (2012) Integrin a5b1 activates the NLRP3 inflammasome by direct interaction with a bacterial surface protein. Immunity 36:755–768. https://doi.org/10.1016/j.immuni.2012.05.002 CrossRefPubMed

30.

Hoffman HM, Rosengren S, Boyle DL et al (2004) Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364:1779–1785. https://doi.org/10.1016/S0140-6736(04)17401-1 CrossRefPubMedPubMedCentral

31.

Dinarello CA (2005) Blocking IL-1 in systemic inflammation. J Exp Med 201:1355–1359. https://doi.org/10.1084/jem.20050640 CrossRefPubMedPubMedCentral

32.

Campa C, Costagliola C, Incorvaia C et al (2010) Inflammatory mediators and angiogenic factors in choroidal neovascularization: pathogenetic interactions and therapeutic implications. Mediat Inflamm 2010. https://doi.org/10.1155/2010/546826

33.

Parmeggiani F, Sorrentino FS, Romano MR et al (2013) Mechanism of inflammation in age-related macular degeneration: an up-to-date on genetic landmarks. Mediat Inflamm 2013. https://doi.org/10.1155/2013/435607

34.

Yang F, Wang Z, Wei X et al (2014) NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab 34:660–667. https://doi.org/10.1038/jcbfm.2013.242 CrossRefPubMedPubMedCentral

35.

Mohamed IN, Ishrat T, Fagan SC et al (2015) Role of inflammasome activation in the pathophysiology of vascular diseases of the neurovascular unit. Antioxid Redox Signal 22:1188–1206. https://doi.org/10.1089/ars.2014.6126 CrossRefPubMedPubMedCentral

36.

Thinwa J, Segovia JA, Bose S et al (2014) Integrin-mediated first signal for inflammasome-activation in intestinal epithelial cells. J Immunol 193:1373–1382. https://doi.org/10.4049/jimmunol.1400145 CrossRefPubMedPubMedCentral

Title: Inhibition of integrin α5β1 ameliorates VEGF-induced retinal neovascularization and leakage by suppressing NLRP3 inflammasome signaling in a mouse model
Authors: Ailing Sui
Yisheng Zhong
Anna M. Demetriades
Qing Lu
Yujuan Cai
Yushuo Gao
Yanji Zhu
Xi Shen
Bing Xie
Publication date: 01-05-2018
Publisher: Springer Berlin Heidelberg
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 5/2018
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-018-3940-x

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Inhibition of integrin α5β1 ameliorates VEGF-induced retinal neovascularization and leakage by suppressing NLRP3 inflammasome signaling in a mouse model

Abstract

Purpose

Method

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Method

Results

Conclusion

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