NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration

International Journal of Molecular Sciences

Yujuan Wang²  Jakub W. Hanus¹  Mones S. Abu-Asab⁵  Defen Shen²  Alexander Ogilvy⁵  Jingxing Ou³  Xi K. Chu²  Guangpu Shi⁴  Wei Li³  Shusheng Wang¹  Chi-Chao Chan² 

[1] Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA;Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA;Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA;Experimental Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA;Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA;

关键词: retina;    oxidative stress;    inflammation;    autophagy;    mitochondria;   

DOI  :  10.3390/ijms17010073

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2016 by the authors; licensee MDPI, Basel, Switzerland.