Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis.
Dendritic cells (DCs) play a pivotal role in the pathogenesis of inflammatory disorders, so suppressing the activity of DCs is instrumental in treating such diseases. In the present study, we show that a proteasome inhibitor, bortezomib, suppresses the survival and immunostimulatory function of human plasmacytoid DCs (pDCs) by targeting 2 critical points, intracellular trafficking of nucleic acid-sensingToll-like receptors (TLRs) and endoplasmic reticulum (ER) homeostasis. Among the immune cells in blood, pDCs were the most susceptible to the killing effect of bortezomib. This correlates with a decrease in the spliced form of a transcription factor XBP1, which rescues cells from apoptosis by maintaining ER homeostasis. Bortezomib suppressed the production of interferon-α and interleukin-6 by pDCs activated with a TLR9-stimulating CpG DNA and a TLR7-stimulating influenza virus, which appears to be partially independent of apoptosis. Bortezomib inhibited translocation of TLR9 from the ER to endolysosomes but not of an ER membrane protein, Unc93B1, that delivers TLR9 to endolysosomes. Thus, bortezomib suppresses the activity of pDCs by inhibiting intracellular trafficking of TLRs through disrupting the coordinated translocation of TLRs and Unc93B1 and by disturbing ER homeostasis. This study suggests that proteasome inhibitors may alleviate inflammatory disorders such as lupus and psoriasis that involve pDCs.
Hirai
Makiko
M
Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kadowaki
Norimitsu
N
Kitawaki
Toshio
T
Fujita
Haruyuki
H
Takaori-Kondo
Akifumi
A
Fukui
Ryutaro
R
Miyake
Kensuke
K
Maeda
Takahiro
T
Kamihira
Shimeru
S
Miyachi
Yoshiki
Y
Uchiyama
Takashi
T
D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D018613:Microscopy, Confocal; D011480:Protease Inhibitors / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D000071717:X-Box Binding Protein 1
D001897:Boronic Acids; D016207:Cytokines; D004268:DNA-Binding Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D000071701:Regulatory Factor X Transcription Factors; D051193:Toll-Like Receptors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D000069286:Bortezomib