NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration
1
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
2
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
3
Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA
4
Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
5
Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
6
Experimental Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Irmgard Tegeder
Int. J. Mol. Sci. 2016, 17(1), 73; https://doi.org/10.3390/ijms17010073
Received: 13 July 2015 / Revised: 29 December 2015 / Accepted: 30 December 2015 / Published: 8 January 2016
(This article belongs to the Section Biochemistry)
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. View Full-TextKeywords:
retina; oxidative stress; inflammation; autophagy; mitochondria
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Wang, Y.; Hanus, J.W.; Abu-Asab, M.S.; Shen, D.; Ogilvy, A.; Ou, J.; Chu, X.K.; Shi, G.; Li, W.; Wang, S.; Chan, C.-C. NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration. Int. J. Mol. Sci. 2016, 17, 73.
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