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Targeted Delivery of Curcumin Rescues Endoplasmic Reticulum-Retained Mutant NOX2 Protein and Avoids Leukocyte Apoptosis.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 Jun 15; Vol. 202 (12), pp. 3394-3403. Date of Electronic Publication: 2019 May 13. - Publication Year :
- 2019
-
Abstract
- Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by defects in the leukocyte NADP oxidase. We previously reported that sarcoplasmic/endoplasmic reticulum calcium pump (SERCA) inhibitors could be used to rescue mutant H338Y-gp91phox protein of a particular type of CGD with a Cybb <superscript>C1024T</superscript> mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the Cybb <superscript>C1024T</superscript> mutation on a Cybb knockout background and investigated the therapeutic effects of ER-targeted delivery of the SERCA inhibitor, curcumin, with poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs). We found that PLGA encapsulation improved the efficacy of curcumin as a SERCA inhibitor to induce ER calcium release. ER-targeting curcumin-loaded PLGA NPs reduced and delayed extracellular calcium entry and protected the cells from mitochondrial damage and apoptosis. In vivo studies showed that ER-targeting curcumin-loaded PLGA NPs treatment enhanced neutrophil gp91phox expression, ROS production and peritoneal bacterial clearance ability of the Cybb <superscript>C1024T</superscript> transgenic Cybb <superscript>-/-</superscript> mice. Our findings indicate that ER-targeted delivery of curcumin not only rescues ER-retained H338Y-gp91phox protein, and hence leukocyte function, but also enhances the bioavailability and reduces cytotoxicity. Modulation of ER function by using organelle-targeted NPs may be a promising strategy to improve the therapeutic potential of curcumin as a treatment for CGD.<br /> (Copyright © 2019 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
Apoptosis
Biological Availability
Curcumin pharmacology
Disease Models, Animal
Drug Delivery Systems
Granulomatous Disease, Chronic immunology
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation genetics
NADPH Oxidase 2 genetics
Nanoparticles chemistry
Polylactic Acid-Polyglycolic Acid Copolymer chemistry
Sarcoplasmic Reticulum Calcium-Transporting ATPases antagonists & inhibitors
Curcumin therapeutic use
Endoplasmic Reticulum metabolism
Granulomatous Disease, Chronic therapy
Leukocytes immunology
NADPH Oxidase 2 metabolism
Nanoparticles therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 202
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 31085592
- Full Text :
- https://doi.org/10.4049/jimmunol.1801599