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Horm Metab Res 2018; 50(09): 704-710
DOI: 10.1055/a-0664-0699
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Prostaglandin E2 Activates NLRP3 Inflammasome in Endothelial Cells to Promote Diabetic Retinopathy

Yixin Wang
1   Department of Ophthalmology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, P. R. China
,
Jianxin Tao
1   Department of Ophthalmology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, P. R. China
,
Yong Yao
1   Department of Ophthalmology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, P. R. China
› Author Affiliations
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Publication History

received 06 March 2018

accepted 19 July 2018

Publication Date:
24 August 2018 (online)

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Abstract

Proliferative diabetic retinopathy (PDR) is the leading cause of blindness and accounts for approximately 12% of all new cases of blindness. Prostaglandin E2 (PGE2) and nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) inflammasomes have been long considered to be associated with PDR. Levels of pro-inflammatory mediators were examined by Enzyme-linked immunosorbent assay (ELISA) measurements. PGE2 levels were analyzed by using the Prostaglandin E2 Monoclonal EIA Kit. Human retinal microvascular endothelial cells (HRMECs) were stained with Annexin V/propidium iodide and analyzed by flow cytometry for testing the apoptosis. Expression levels of NLRP3 inflammasome components under various conditions were detected by Western blot and real-time PCR. Inflammasome markers and PGE2 were highly expressed in the vitreous of PDR patients. PGE2 and NLRP3 induced apoptosis of HRMECs. PGE2 upregulated the expression of NLRP3 inflammasome components and inflammatory chemokines. Knockdown of NLRP3 attenuated the expression of NLRP3 inflammasome components and inhibited the effect of PGE2. Our results suggest that PGE2 levels and NLRP3 inflammasome activation are closely related to the pathogenesis of PDR and nonsteroidal anti-inflammatory drugs may have a potential therapeutic effect on PDR.

Key words

proliferative diabetic retinopathy (PDR) - NLRP3 inflammasomes - prostaglandin E2 (PGE2) - apoptosis
 

  • References

  • 1 Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med 2012; 366: 1227-1239
    CrossrefPubMedSearch in Google Scholar
  • 2 Ting DS, Tan KA, Phua V, Tan GS, Wong CW, Wong TY. Biomarkers of diabetic retinopathy. Curr Diab Rep 2016; 16: 125
    CrossrefPubMedSearch in Google Scholar
  • 3 Fukushima H, Kato S. [Diabetic retinopathy]. Nihon Rinsho 2015; 73: 2032-2036
    PubMedSearch in Google Scholar
  • 4 Blackhall K. Searching for evidence-based information in eye care. Comm Eye Health 2005; 18: 126-127
    PubMedSearch in Google Scholar
  • 5 [Anonymous]. Diabetic retinopathy. Community Eye Health 2011; 24: 23
    PubMedSearch in Google Scholar
  • 6 Mohamed QA, Ross A, Chu CJ. Diabetic retinopathy (treatment). BMJ Clin Evid 2011 pii0702
    PubMed
  • 7 Engelgau MM, Geiss LS, Saaddine JB, Boyle JP, Benjamin SM, Gregg EW, Tierney EF, Rios-Burrows N, Mokdad AH, Ford ES, Imperatore G, Narayan KM. The evolving diabetes burden in the United States. Ann Intern Med 2004; 140: 945-950
    PubMedSearch in Google Scholar
  • 8 [Anonymous]. Pharmacology of prostaglandins, in brief. Prescrire Int 2015; 24: 184
    PubMed
  • 9 Kawahara K, Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y. Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors. Biochim Biophys Acta 2015; 1851: 414-421
    PubMedSearch in Google Scholar
  • 10 Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol 2010; 55: 108-133
    CrossrefPubMedSearch in Google Scholar
  • 11 Reddy R, Kim SJ. Critical appraisal of ophthalmic ketorolac in treatment of pain and inflammation following cataract surgery. Clin Ophthalmol 2011; 5: 751-758
    PubMedSearch in Google Scholar
  • 12 Dai Y, Zhang X, Peng Y, Wang Z. The expression of cyclooxygenase-2, VEGF and PGs in CIN and cervical carcinoma. Gynecol Oncol 2005; 97: 96-103
    CrossrefPubMedSearch in Google Scholar
  • 13 Schoenberger SD, Kim SJ, Sheng J, Rezaei KA, Lalezary M, Cherney E. Increased prostaglandin E2 (PGE2) levels in proliferative diabetic retinopathy, and correlation with VEGF and inflammatory cytokines. Invest Ophthalmol Vis Sci 2012; 53: 5906-5911
    CrossrefPubMedSearch in Google Scholar
  • 14 Martinon F, Burns K, Tschopp J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10: 417-426
    CrossrefPubMedSearch in Google Scholar
  • 15 Netea MG, van der Meer JW. Immunodeficiency and genetic defects of pattern-recognition receptors. N Engl J Med 2011; 364: 60-70
    CrossrefPubMedSearch in Google Scholar
  • 16 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140: 805-820
    CrossrefPubMedSearch in Google Scholar
  • 17 Loukovaara S, Piippo N, Kinnunen K, Hytti M, Kaarniranta K, Kauppinen A. NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy. Acta Ophthalmol 2017; 95: 803-808
    CrossrefPubMedSearch in Google Scholar
  • 18 Sinova I, Chrapek O, Mlcak P, Rehak J, Karhanova M, Sin M. [Automatic Retinal Oxymetry in Patients with Diabetic Retinopathy]. Cesk Slov Oftalmol. 72: 182-186
    PubMed
  • 19 Amin J, Sharif M, Yasmin M. A Review on Recent Developments for Detection of Diabetic Retinopathy. Scientifica (Cairo) 2016; 6838976:
    PubMed
  • 20 Bek T. Mitochondrial dysfunction and diabetic retinopathy. Mitochondrion 2017; 36: 4-6
    CrossrefPubMedSearch in Google Scholar
  • 21 Capitao M, Soares R. Angiogenesis and Inflammation Crosstalk in Diabetic Retinopathy. J Cell Biochem 2016; 117: 2443-2453
    CrossrefPubMedSearch in Google Scholar
  • 22 Cleland CR, Burton MJ, Hall C, Hall A, Courtright P, Makupa WU, Philippin H. Diabetic retinopathy in Tanzania: Prevalence and risk factors at entry into a regional screening programme. Trop Med Int Health 2016; 21: 417-426
    CrossrefPubMedSearch in Google Scholar
  • 23 Das A. Diabetic retinopathy: Battling the global epidemic. Indian J Ophthalmol 2016; 64: 2-3
    CrossrefPubMedSearch in Google Scholar
  • 24 Bandello F, Corvi F, La Spina C, Benatti L, Querques L, Capuano V, Naysan J, Chen X, Sarraf D, Parodi MB, Souied E, Freund KB, Querques G. Outcomes of intravitreal anti-VEGF therapy in eyes with both neovascular age-related macular degeneration and diabetic retinopathy. Br J Ophthalmol 2016; 100: 1611-1616
    CrossrefPubMedSearch in Google Scholar
  • 25 Cai X, McGinnis JF. Diabetic Retinopathy: Animal Models, Therapies, and Perspectives. J Diabetes Res 2016; 3789217:
    PubMed
  • 26 Loukovaara S, Gucciardo E, Repo P, Vihinen H, Lohi J, Jokitalo E, Salven P, Lehti K. Indications of lymphatic endothelial differentiation and endothelial progenitor cell activation in the pathology of proliferative diabetic retinopathy. Acta Ophthalmol 2015; 93: 512-523
    CrossrefPubMedSearch in Google Scholar
  • 27 Yoshimura N, Jimba M, Poudel KC, Chanthavisouk C, Iwamoto A, Phommasack B, Saklokham K. Health promoting schools in urban, semi-urban and rural Lao PDR. Health Promot Int 2009; 24: 166-176
    CrossrefPubMedSearch in Google Scholar
  • 28 Loukovaara S, Sahanne S, Jalkanen S, Yegutkin GG. Increased intravitreal adenosine 5'-triphosphate, adenosine 5'-diphosphate and adenosine 5'-monophosphate levels in patients with proliferative diabetic retinopathy. Acta Ophthalmol 2015; 93: 67-73
    CrossrefPubMedSearch in Google Scholar
  • 29 Neurath MF, Finotto S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 2011; 22: 83-89
    CrossrefPubMedSearch in Google Scholar
  • 30 Suzuki Y, Nakazawa M, Suzuki K, Yamazaki H, Miyagawa Y. Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion. Jpn J Ophthalmol 2011; 55: 256-263
    CrossrefPubMedSearch in Google Scholar
  • 31 Yang G, Chen L. An Update of Microsomal Prostaglandin E Synthase-1 and PGE2 Receptors in Cardiovascular Health and Diseases. Oxid Med Cell Longev 2016; 2016: 5249086
    PubMedSearch in Google Scholar
  • 32 Rosatti F, Lampa E, Spaziante G, Magliulo S, Giasi M, Imperatore A, Montanino C, Scognamiglio A, Marmo E. [Experimental analysis of the cardiovascular and respiratory effects of PGE2 in gastric administration]. Arch Ostet Ginecol 1979; 84: 185-202
    PubMedSearch in Google Scholar
  • 33 Nasrallah R, Hassouneh R, Hebert RL. PGE2, kidney disease, and cardiovascular risk: Beyond hypertension and diabetes. J Am Soc Nephrol 2016; 27: 666-676
    CrossrefPubMedSearch in Google Scholar
  • 34 Lai FM, Tanikella TK, Herzlinger H, Shepherd C, Cervoni P. Effects of CL 115,347, (+/–)-15-deoxy-16-hydroxy-16-vinyl-PGE2 methyl ester, on cardiovascular responses and plasma catecholamines in pithed stroke-prone spontaneously hypertensive rats during sympathetic stimulation. Prostaglandins 1984; 27: 273-284
    CrossrefPubMedSearch in Google Scholar
  • 35 Karlsson JA, Sant'Ambrogio FB, Forsberg K, Palecek F, Mathew OP, Sant'Ambrogio G. Respiratory and cardiovascular effects of inhaled and intravenous bradykinin, PGE2, and PGF2 alpha in dogs. J Appl Physiol (1985) 1993; 74: 2380-2386
    CrossrefPubMedSearch in Google Scholar
  • 36 Horzela T, Dubiel JS, Dubiel JP, Pyzik Z, Mysik M, Kolasinska-Kloch W. [Effect of a methylated derivative of prostaglandin E2 (16,16-dimethyl PGE2) on the human cardiovascular system]. Pol Arch Med Wewn 1981; 66: 343-351
    PubMedSearch in Google Scholar
  • 37 Nagano T, Kimura SH, Takemura M. Prostaglandin E2 induces apoptosis in cultured rat microglia. Brain Res 2014; 1568: 1-9
    CrossrefPubMedSearch in Google Scholar
  • 38 Coulombe F, Jaworska J, Verway M, Tzelepis F, Massoud A, Gillard J, Wong G, Kobinger G, Xing Z, Couture C, Joubert P, Fritz JH, Powell WS, Divangahi M. Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages. Immunity 2014; 40: 554-568
    CrossrefPubMedSearch in Google Scholar
  • 39 Gupta N, Mansoor S, Sharma A, Sapkal A, Sheth J, Falatoonzadeh P, Kuppermann B, Kenney M. Diabetic retinopathy and VEGF. Open Ophthalmol J 2013; 7: 4-10
    CrossrefPubMedSearch in Google Scholar
  • 40 Ishida S, Shinoda K, Kawashima S, Oguchi Y, Okada Y, Ikeda E. Coexpression of VEGF receptors VEGF-R2 and neuropilin-1 in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 2000; 41: 1649-1656
    PubMedSearch in Google Scholar
  • 41 Jardeleza MS, Miller JW. Review of anti-VEGF therapy in proliferative diabetic retinopathy. Semin Ophthalmol 2009; 24: 87-92
    CrossrefPubMedSearch in Google Scholar
  • 42 Olsen TW. Anti-VEGF pharmacotherapy as an alternative to panretinal laser photocoagulation for proliferative diabetic retinopathy. JAMA 2015; 314: 2135-2136
    CrossrefPubMedSearch in Google Scholar
  • 43 Gicquel T, Robert S, Victoni T, Lagente V. [The NLRP3 inflammasome: Physiopathology and therapeutic application]. Presse Med 2016; 45: 438-446
    CrossrefPubMedSearch in Google Scholar
  • 44 Baroja-Mazo A, Martin-Sanchez F, Gomez AI, Martinez CM, Amores-Iniesta J, Compan V, Barbera-Cremades M, Yague J, Ruiz-Ortiz E, Anton J, Bujan S, Couillin I, Brough D, Arostegui JI, Pelegrin P. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 2014; 15: 738-748
    CrossrefPubMedSearch in Google Scholar
  • 45 Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, Hoffman HM, Feldstein AE. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 2014; 59: 898-910
    CrossrefPubMedSearch in Google Scholar