title: NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration.
abstract: Inflammation and oxidative stress are involved in age-related macular degeneration (AMD) and possibly associated with an activation of neuronal apoptosis inhibitor protein/class II transcription activator of the Major Histocompatibility Complex (MHC)/heterokaryon incompatibility/telomerase-associated protein 1, leucine-rich repeat or nucleotide-binding domain, leucine-rich repeat-containing family, and pyrin domain-containing 3 (NLRP3) inflammasome. In the present study, we used a translational approach to address this hypothesis. In patients with AMD, we observed increased mRNA levels of NLRP3, pro-interleukin-1 beta (IL-1β) and pro-IL-18 in AMD lesions of the retinal pigment epithelium (RPE) and photoreceptor. In vitro, a similar increase was evoked by oxidative stress or lipopolysaccharide (LPS) stimulation in the adult retinal pigment epithelium (ARPE-19) cell line, and the increase was reduced in siRNA transfected cells to knockdown NLRP3. Ultrastructural studies of ARPE-19 cells showed a swelling of the cytoplasm, mitochondrial damage, and occurrence of autophagosome-like structures. NLRP3 positive dots were detected within autophagosome-like structures or in the extracellular space. Next, we used a mouse model of AMD, Ccl2/Cx3cr1 double knockout on rd8 background (DKO rd8) to ascertain the in vivo relevance. Ultrastructural studies of the RPE of these mice showed damaged mitochondria, autophagosome-like structures, and cytoplasmic vacuoles, which are reminiscent of the pathology seen in stressed ARPE-19 cells. The data suggest that the NLRP3 inflammasome may contribute in AMD pathogenesis.
authors.affiliation: Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. yujuanwang2013@gmail.com.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. yujuanwang2013@gmail.com.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA. jhanus@tulane.edu.
authors.forename: Jakub W
authors.initials: JW
authors.lastname: Hanus
authors.affiliation: Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. mones@nei.nih.gov.
authors.forename: Mones S
authors.initials: MS
authors.lastname: Abu-Asab
authors.affiliation: Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. defen.shen@gmail.com.
authors.forename: Defen
authors.initials: D
authors.lastname: Shen
authors.affiliation: Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. ogilvy.alexander@gmail.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ogilvy
authors.affiliation: Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. ouj@nei.nih.gov.
authors.forename: Jingxing
authors.initials: J
authors.lastname: Ou
authors.affiliation: Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. xi.kathy.chu@gmail.com.
authors.forename: Xi K
authors.initials: XK
authors.lastname: Chu
authors.affiliation: Experimental Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. shig@nei.nih.gov.
authors.forename: Guangpu
authors.initials: G
authors.lastname: Shi
authors.affiliation: Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. liwei2@nei.nih.gov.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA. swang1@tulane.edu.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. chanc@nei.nih.gov.|Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. chanc@nei.nih.gov.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008266:Macula Lutea / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D034741:RNA, Small Interfering
keywords: autophagy; inflammation; mitochondria; oxidative stress; retina