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| Status |
Public on Dec 11, 2022 |
| Title |
IkBNS-deficiency protects mice from Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses [Liver monocytes] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
IkB proteins regulate the inhibition and activation of NF-kB transcription factor complexes. While classical IkB proteins keep NF-kB complexes inactive in the cytoplasm, atypical IkB proteins act on activated NF-kB complexes located in the nucleus. Most of the knowledge regarding the function of IkB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IkBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IkBNS-dependent (Nfkbid gene) reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6C-high inflammatory monocytes prompted us to further characterized the specific contribution of IkBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6C-high monocytes primed during Lm infection in the absence of IkBNS displayed a blunted response compared to wild type-derived Ly6C-high monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il-6, Nos2 and Il1-β. Strikingly, altered monocyte activation in IkBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IkBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IkBNS -/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IkBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IkBNS during Lm infection with IkBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6C-high monocytes. Reduced immunopathology and complete protection of mice against an otherwise lethal Lm infection identified IkBNS as molecular driver of inflammation in listeriosis.
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| Overall design |
WT and IκBNS-/- mice (n = 3 - 5 per group, from two independent experiments) were infected with 3×10^4 CFU Lm i.v., sacrificed on day 3 post infection, liver tissue was enzymatically digested, total leukocytes were isolated using Percoll density gradient centrifugation, Ly6C-high inflammatory monocytes were FACS sorted and pooled per genotype and total RNA was isolated. Transcriptome was analyzed using Affymetrix Mouse Clariom S microarrays.
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| Contributor(s) |
Frentzel S, Jeron A, Pausder A, Kershaw O, Volckmar J, Schmitz I, Bruder D |
| Citation(s) |
36618344 |
| Submission date |
Dec 06, 2022 |
| Last update date |
Jan 13, 2023 |
| Contact name |
Andreas Jeron |
| E-mail(s) |
andreas.jeron@helmholtz-hzi.de
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| Organization name |
Helmholtz Center for Infection Research
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| Department |
Viral Immunology
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| Lab |
Immune Regulation
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| Street address |
Inhoffenstraße 7
|
| City |
Braunschweig |
| State/province |
Nierdersachsen |
| ZIP/Postal code |
38124 |
| Country |
Germany |
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| Platforms (1) |
| GPL23038 |
[Clariom_S_Mouse] Affymetrix Clariom S Assay, Mouse (Includes Pico Assay) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE220267 |
IkBNS-deficiency protects mice from Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses |
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| Relations |
| BioProject |
PRJNA909331 |
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