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| Status |
Public on May 16, 2020 |
| Title |
IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The IRE1α-XBP1 arm of the unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis, but also controls UPR-independent processes such as cytokine production and lipid metabolism. Yet, the physiological consequences of IRE1α-XBP1 activation in immune cells remain largely unexplored. Here, we report that leukocyte-intrinsic IRE1α-XBP1 signaling drives prostaglandin biosynthesis and pain. Transcriptomic analyses revealed that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated via pattern recognition receptors. Inducible biosynthesis of prostaglandins, including PGE2, was markedly decreased in myeloid cells lacking IRE1α or XBP1, but not altered in the absence of the two other ER stress sensors PERK and ATF6. Mechanistically, IRE1α-activated XBP1 bound to and directly induced the expression of human PTGS2 and PTGES to enable PGE2 generation. Mice selectively lacking IRE1α-XBP1 in leukocytes, or treated with pharmacological IRE1α inhibitors, failed to induce PGE2 upon challenge with inflammatory stimuli and demonstrated reduced behavioral pain responses in PGE2-dependent models of pain. Our study uncovers an unexpected role for IRE1α-XBP1 as a key mediator of prostaglandin biosynthesis and indicates that targeting this pathway may represent an alternative approach to control pain.
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| Overall design |
RNA-seq for bone marrow derived dendritic cells from mice untreated and treated with Zymosan and LPS in IRE1α wild type and knockout conditions
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| Contributor(s) |
Chopra S, Cubillos-Ruiz JR |
| Citation(s) |
31320508 |
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| Submission date |
May 17, 2019 |
| Last update date |
Aug 17, 2020 |
| Contact name |
Priyankara J Wickramasinghe |
| E-mail(s) |
priyaw@wistar.org
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| Phone |
2154956837
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| Organization name |
The Wistar Institute
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| Department |
Bioinformatics
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| Lab |
Genomics
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| Street address |
3601 Spruce Street
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (24)
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| GSM3774171 |
Dendritic cells from IRE1 wild type untreated mice, replicate 1 |
| GSM3774172 |
Dendritic cells from IRE1 wild type untreated mice, replicate 2 |
| GSM3774173 |
Dendritic cells from IRE1 wild type untreated mice, replicate 3 |
| GSM3774174 |
Dendritic cells from IRE1 wild type untreated mice, replicate 4 |
| GSM3774175 |
Dendritic cells from IRE1 wild type mice treated with Zymosan, replicate 1 |
| GSM3774176 |
Dendritic cells from IRE1 wild type mice treated with Zymosan, replicate 2 |
| GSM3774177 |
Dendritic cells from IRE1 wild type mice treated with Zymosan, replicate 3 |
| GSM3774178 |
Dendritic cells from IRE1 wild type mice treated with Zymosan, replicate 4 |
| GSM3774179 |
Dendritic cells from IRE1 wild type mice treated with LPS, replicate 1 |
| GSM3774180 |
Dendritic cells from IRE1 wild type mice treated with LPS, replicate 2 |
| GSM3774181 |
Dendritic cells from IRE1 wild type mice treated with LPS, replicate 3 |
| GSM3774182 |
Dendritic cells from IRE1 wild type mice treated with LPS, replicate 4 |
| GSM3774183 |
Dendritic cells from IRE1 knock out untreated mice, replicate 1 |
| GSM3774184 |
Dendritic cells from IRE1 knock out untreated mice, replicate 2 |
| GSM3774185 |
Dendritic cells from IRE1 knock out untreated mice, replicate 3 |
| GSM3774186 |
Dendritic cells from IRE1 knock out untreated mice, replicate 4 |
| GSM3774187 |
Dendritic cells from IRE1 knock out mice treated with Zymosan, replicate 1 |
| GSM3774188 |
Dendritic cells from IRE1 knock out mice treated with Zymosan, replicate 2 |
| GSM3774189 |
Dendritic cells from IRE1 knock out mice treated with Zymosan, replicate 3 |
| GSM3774190 |
Dendritic cells from IRE1 knock out mice treated with Zymosan, replicate 4 |
| GSM3774191 |
Dendritic cells from IRE1 knock out mice treated with LPS, replicate 1 |
| GSM3774192 |
Dendritic cells from IRE1 knock out mice treated with LPS, replicate 2 |
| GSM3774193 |
Dendritic cells from IRE1 knock out mice treated with LPS, replicate 3 |
| GSM3774194 |
Dendritic cells from IRE1 knock out mice treated with LPS, replicate 4 |
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| Relations |
| BioProject |
PRJNA543490 |
| SRA |
SRP198767 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE131404_GEO_Cubillos_DC_IRE1_data.txt.gz |
843.0 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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