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| Status |
Public on Jul 09, 2021 |
| Title |
Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Intercellular transmission of the second messenger 2′,3′‐cGAMP, synthesized by the viral DNA sensor cGAMP synthase (cGAS), is a potent mode of bystander activation during host defense. However, whether this mechanism also contributes to cGAS-dependent autoimmunity remains unknown. Here, using a murine bone marrow transplantation strategy, we demonstrate that, in Trex1-/--associated autoimmunity, cGAMP shuttling from radioresistant to immune cells induces NF-κB activation, interferon regulatory protein 3 (IRF3) phosphorylation and subsequent interferon signaling. cGAMP travel prevented myeloid cell and lymphocyte death, promoting their accumulation in secondary lymphoid tissue. Nonetheless, it did not stimulate B cell differentiation into autoantibody-producing plasmablasts or aberrant T cell priming in the steady state. Although cGAMP-mediated bystander activation did not induce spontaneous organ disease, it did trigger interface dermatitis after UV light exposure, similar to cutaneous lupus erythematosus. These findings reveal that, in Trex1-deficiency, intercellular cGAMP transfer propagates cGAS signaling and, under conducive conditions, causes tissue inflammation.
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| Overall design |
Total RNA was isolated from single-cell suspensions of bone marrow from Cgas-/- mice and Trex1-/-;Sting1gt/gt mice (called dKO). In addition, total RNA was isolated from single-cell suspensions of spleens from dKO mice 12 weeks after they were lethally irradiated and transplanted with Cgas-/- or dKO bone marrow. 3'-mRNA Seq was performed on an Illumina HiSeq 2500.
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| Contributor(s) |
Jütte BB, Koerber R, Gräf CM, Teichmann LL |
| Citation(s) |
34368651 |
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| Submission date |
Jun 06, 2021 |
| Last update date |
Aug 11, 2021 |
| Contact name |
Lino Lars Teichmann |
| E-mail(s) |
[email protected]
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| Organization name |
University Hospital Bonn
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| Department |
Department of Medicine III
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| Street address |
Venusberg-Campus 1
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| City |
Bonn |
| ZIP/Postal code |
53127 |
| Country |
Germany |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA735518 |
| SRA |
SRP322915 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE176225_DESeq2_results_BM_CgasKO_vs_dKO.csv.gz |
874.1 Kb |
(ftp)(http) |
CSV |
| GSE176225_DESeq2_results_spleen_CgasKO-BM-Tx_vs_dKO-BM-Tx.csv.gz |
1.2 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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