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| Status |
Public on Feb 19, 2024 |
| Title |
Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
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| Overall design |
To investigate the anti inflammatory effect of glucocortidcoids we performed RNA sequencing of LPS treated bone marrow derived macrophages in the absence and presence of glucocorticoids. Additionally, we performed RNA sequencing of IRG1 Knockout mice using the same conditions.
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| Contributor(s) |
Auger J, Zimmermann M, Faas M, Stifel U, Chambers D, Krishnacoumar B, Taudte R, Grund C, Erdmann G, Scholtysek C, Uderhardt S, Ben Brahim O, Pascual Maté M, Stoll C, Böttcher M, Palumbo-Zerr K, Mangan M, Dzamukova M, Kieler M, Hofmann M, Blüml S, Schabbauer G, Mougiakakos D, Sonnewald U, Hartmann F, Simon D, Kleyer A, Grüneboom A, Finotto S, Latz E, Hofmann J, Schett G, Tuckermann J, Krönke G |
| Citation(s) |
38600378 |
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| Submission date |
Dec 15, 2023 |
| Last update date |
May 10, 2024 |
| Contact name |
Artur Wilhelm |
| E-mail(s) |
Artur.wilhelm@charite.de
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| Organization name |
Charite Berlin
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| Department |
Rheumatology and clinical immunology
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| Lab |
AG Krönke
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| Street address |
Virchowweg 11
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| City |
Berlin |
| ZIP/Postal code |
10117 |
| Country |
Germany |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (32)
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| GSM7976577 |
Sample1_BMDM cells, Control, 24h, Acod1 WT, replicate #1 |
| GSM7976578 |
Sample2_BMDM cells, Control, 24h, Acod1 WT, replicate #2 |
| GSM7976579 |
Sample3_BMDM cells, Control, 24h, Acod1 WT, replicate #3 |
| GSM7976580 |
Sample4_BMDM cells, Control, 24h, Acod1 WT, replicate #4 |
| GSM7976581 |
Sample5_BMDM cells, Glucocorticoid stimulated, 24h, Acod1 WT, replicate #1 |
| GSM7976582 |
Sample6_BMDM cells, Glucocorticoid stimulated, 24h, Acod1 WT, replicate #2 |
| GSM7976583 |
Sample7_BMDM cells, Glucocorticoid stimulated, 24h, Acod1 WT, replicate #3 |
| GSM7976584 |
Sample8_BMDM cells, Glucocorticoid stimulated, 24h, Acod1 WT, replicate #4 |
| GSM7976585 |
Sample9_BMDM cells, LPS stimulated, 24h, Acod1 WT, replicate #1 |
| GSM7976586 |
Sample10_BMDM cells, LPS stimulated, 24h, Acod1 WT, replicate #2 |
| GSM7976587 |
Sample11_BMDM cells, LPS stimulated, 24h, Acod1 WT, replicate #3 |
| GSM7976588 |
Sample12_BMDM cells, LPS stimulated, 24h, Acod1 WT, replicate #4 |
| GSM7976589 |
Sample13_BMDM cells, Glucocorticoid+LPS stimulated, 24h, Acod1 WT, replicate #1 |
| GSM7976590 |
Sample14_BMDM cells, Glucocorticoid+LPS stimulated, 24h, Acod1 WT, replicate #2 |
| GSM7976591 |
Sample15_BMDM cells, Glucocorticoid+LPS stimulated, 24h, Acod1 WT, replicate #3 |
| GSM7976592 |
Sample16_BMDM cells, Glucocorticoid+LPS stimulated, 24h, Acod1 WT, replicate #4 |
| GSM7976593 |
Sample17_BMDM cells, Control, 24h, Acod1 KO, replicate #1 |
| GSM7976594 |
Sample18_BMDM cells, Control, 24h, Acod1 KO, replicate #2 |
| GSM7976595 |
Sample19_BMDM cells, Control, 24h, Acod1 KO, replicate #3 |
| GSM7976596 |
Sample20_BMDM cells, Control, 24h, Acod1 KO, replicate #4 |
| GSM7976597 |
Sample21_BMDM cells, Glucocorticoid stimulated, 24h, Acod1 KO, replicate #1 |
| GSM7976598 |
Sample22_BMDM cells, Glucocorticoid stimulated, 24h, Acod1 KO, replicate #2 |
| GSM7976599 |
Sample23_BMDM cells, Glucocorticoid stimulated, 24h, Acod1 KO, replicate #3 |
| GSM7976600 |
Sample24_BMDM cells, Glucocorticoid stimulated, 24h, Acod1 KO, replicate #4 |
| GSM7976601 |
Sample25_BMDM cells, LPS stimulated, 24h, Acod1 KO, replicate #1 |
| GSM7976602 |
Sample26_BMDM cells, LPS stimulated, 24h, Acod1 KO, replicate #2 |
| GSM7976603 |
Sample27_BMDM cells, LPS stimulated, 24h, Acod1 KO, replicate #3 |
| GSM7976604 |
Sample28_BMDM cells, LPS stimulated, 24h, Acod1 KO, replicate #4 |
| GSM7976605 |
Sample29_BMDM cells, Glucocorticoid+LPS stimulated, 24h, Acod1 KO, replicate #1 |
| GSM7976606 |
Sample30_BMDM cells, Glucocorticoid+LPS stimulated, 24h, Acod1 KO, replicate #2 |
| GSM7976607 |
Sample31_BMDM cells, Glucocorticoid+LPS stimulated, 24h, Acod1 KO, replicate #3 |
| GSM7976608 |
Sample32_BMDM cells, Glucocorticoid+LPS stimulated, 24h, Acod1 KO, replicate #4 |
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| Relations |
| BioProject |
PRJNA1053280 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE250274_genecount.txt.gz |
4.9 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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