Targeted delivery of curcumin rescues endoplasmic reticulum-retained mutant Nox2 protein and avoids leukocyte apoptosis

Chia Liang Yen, Yi Chu Liao, Ru Fen Chen, Ya Fang Huang, Wan Chen Chung, Pei Chi Lo, Chuan Fa Chang, Ping Ching Wu, Dar Bin Shieh, Si Tse Jiang, Chi Chang Shieh

研究成果: Article

摘要

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.

原文English
頁(從 - 到)3394-3403
頁數10
期刊Journal of Immunology
202
發行號12
DOIs
出版狀態Published - 2019 六月 15

指紋

Curcumin
Mutant Proteins
Endoplasmic Reticulum
Leukocytes
Apoptosis
Chronic Granulomatous Disease
Nanoparticles
Calcium
Sarcoplasmic Reticulum
Mutation
Therapeutic Uses
NADP
Organelles
Biological Availability
Oxidoreductases
Proteins
Neutrophils

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

引用此文

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title = "Targeted delivery of curcumin rescues endoplasmic reticulum-retained mutant Nox2 protein and avoids leukocyte apoptosis",
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.",
author = "Yen, {Chia Liang} and Liao, {Yi Chu} and Chen, {Ru Fen} and Huang, {Ya Fang} and Chung, {Wan Chen} and Lo, {Pei Chi} and Chang, {Chuan Fa} and Wu, {Ping Ching} and Shieh, {Dar Bin} and Jiang, {Si Tse} and Shieh, {Chi Chang}",
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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.

於: Journal of Immunology, 卷 202, 編號 12, 15.06.2019, p. 3394-3403.

研究成果: Article

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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.

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