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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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 languageEnglish
Pages (from-to)3394-3403
Number of pages10
JournalJournal of Immunology
Volume202
Issue number12
DOIs
Publication statusPublished - 2019 Jun 15

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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