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 CybbC1024T mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the CybbC1024T 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 CybbC1024T transgenic Cybb2/2 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.
| Original language | English |
|---|---|
| Pages (from-to) | 3394-3403 |
| Number of pages | 10 |
| Journal | Journal of Immunology |
| Volume | 202 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2019 Jun 15 |
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All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Immunology
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Targeted delivery of curcumin rescues endoplasmic reticulum-retained mutant Nox2 protein and avoids leukocyte apoptosis. / Yen, Chia Liang; Liao, Yi Chu; Chen, Ru Fen; Huang, Ya Fang; Chung, Wan Chen; Lo, Pei Chi; Chang, Chuan Fa; Wu, Ping Ching; Shieh, Dar Bin; Jiang, Si Tse; Shieh, Chi Chang.
In: Journal of Immunology, Vol. 202, No. 12, 15.06.2019, p. 3394-3403.Research output: Contribution to journal › Article
TY - JOUR
T1 - Targeted delivery of curcumin rescues endoplasmic reticulum-retained mutant Nox2 protein and avoids leukocyte apoptosis
AU - Yen, Chia Liang
AU - Liao, Yi Chu
AU - Chen, Ru Fen
AU - Huang, Ya Fang
AU - Chung, Wan Chen
AU - Lo, Pei Chi
AU - Chang, Chuan Fa
AU - Wu, Ping Ching
AU - Shieh, Dar Bin
AU - Jiang, Si Tse
AU - Shieh, Chi Chang
PY - 2019/6/15
Y1 - 2019/6/15
N2 - 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 CybbC1024T mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the CybbC1024T 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 CybbC1024T transgenic Cybb2/2 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.
AB - 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 CybbC1024T mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the CybbC1024T 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 CybbC1024T transgenic Cybb2/2 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.
UR - http://www.scopus.com/inward/record.url?scp=85067218212&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067218212&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1801599
DO - 10.4049/jimmunol.1801599
M3 - Article
C2 - 31085592
AN - SCOPUS:85067218212
VL - 202
SP - 3394
EP - 3403
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 12
ER -