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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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE220267 | GEO | 2022/12/11
REPOSITORIES: GEO
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Project description: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.
2022-12-11 | GSE220266 | GEO
Project description: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 (Nfkbid gene) was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IkBNS-dependent 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.
2022-12-11 | GSE220265 | GEO
Project description:IkBNS-deficiency protects mice from Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses
| PRJNA909325 | ENA
Project description:IkBNS-deficiency protects mice from Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses [Liver monocytes]
| PRJNA909331 | ENA
Project description:IkBNS-deficiency protects mice from Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses [Liver]
| PRJNA909327 | ENA
Project description:The gut microbiota and microRNAs play important roles in the defense against infection. However, the role of miR-146a in L. monocytogenes infection and gut microbiota remains unclear. We tried to determine whether miR-146a controlled L. monocytogenes infection by regulating the gut microbiota. Wild-type and miR-146a-deficient mice or macrophages were used to characterize the impact of miR-146a on animal survival, cell death, bacterial clearance, and gut microbiota following L. monocytogenes challenge. We found that L. monocytogenes infection induced miR-146a expression both in vitro and in vivo. When compared to wild-type mice, miR-146a-deficient mice were more resistant to L. monocytogenes infection. MiR-146a deficiency in macrophages resulted in reduced invasion and intracellular survival of L. monocytogenes. High-throughput sequencing of 16S rRNA revealed that the gut microbiota composition differed between miR-146a-deficient and wild-type mice. Relative to wild-type mice, miR-146a-deficient mice had decreased levels of the Proteobacteria phylum, Prevotellaceae family, and Parasutterella genus, and significantly increased short-chain fatty acid producing bacteria, including the genera Alistipes, Blautia, Coprococcus_1, and Ruminococcus_1. Wild-type mice co-housed with miR-146a-deficient mice had increased resistance to L. monocytogenes, indicating that miR-146a deficiency guides the gut microbiota to alleviate infection. Together, these results suggest that miR-146a deficiency protects against L. monocytogenes infection by regulating the gut microbiota.
| S-EPMC5979314 | biostudies-literature
Project description:BackgroundSusceptibility or resistance to infection with Listeria monocytogenes correlates with Selenium (Se) deficiency in response to infection.ResultsSe-deficient mouse models of listeriosis were used to study the innate immune response during the course of L. monocytogenes infection. Blood samples from mouse models were used for Se status. The concentration of MDA, SOD, GPx and CAT in blood has revealed that lower Se level exist in Se-deficient mice. Intestine, mesenteric lymph node, liver, spleen and brain from each mouse were to study the bacterial burden in organs. The analysis of cell types of spleen from Se-deficient mice revealed that the ability of the host to elicit a rapid recruitment and activation of systemic innate immune response to infection was to a certain extent compromised under conditions of Se deficiency. The cytokine levels in the serum and cytokine expression levels in the livers from Se-deficient mice revealed that the innate immune response of Se-deficient mice was impaired throughout the course of infection. These results suggest that innate immune response is altered by Se deficiency after infection with L. monocytogenes.ConclusionIn conclusion, induced susceptibility of host resistance is associated with an impaired innate immune response following infection with L. monocytogenes in C57BL/6 Se-deficient mice.
| S-EPMC2774297 | biostudies-literature
Project description:CD38, adenosine-5'-diphosphate-ribosyl cyclase 1, is a multifunctional enzyme, expressed on a wide variety of cell types. CD38 has been assigned diverse functions, including generation of calcium-mobilizing metabolites, cell activation, and chemotaxis. Using a murine Listeria monocytogenes infection model, we found that CD38 knockout (KO) mice were highly susceptible to infection. Enhanced susceptibility was already evident within 3 days of infection, suggesting a function of CD38 in the innate immune response. CD38 was expressed on neutrophils and inflammatory monocytes, and especially inflammatory monocytes further upregulated CD38 during infection. Absence of CD38 caused alterations of the migration pattern of both cell types to sites of infection. We observed impaired accumulation of cells in the spleen but surprisingly similar or even higher accumulation of cells in the liver. CD38 KO and wild-type mice showed similar changes in the composition of neutrophils and inflammatory monocytes in blood and bone marrow, indicating that mobilization of these cells from the bone marrow was CD38 independent. In vitro, macrophages of CD38 KO mice were less efficient in uptake of listeria but still able to kill the bacteria. Dendritic cells also displayed enhanced CD38 expression following infection. However, absence of CD38 did not impair the capacity of mice to prime CD8(+) T cells against L. monocytogenes, and CD38 KO mice could efficiently control secondary listeria infection. In conclusion, our results demonstrate an essential role for CD38 in the innate immune response against L. monocytogenes.
| S-EPMC3811837 | biostudies-literature
Project description:Mammalian pregnancy requires protection against immunological rejection of the developing fetus bearing discordant paternal antigens. Immune evasion in this developmental context entails silenced expression of chemoattractant proteins (chemokines), thereby preventing harmful immune cells from penetrating the maternal-fetal interface. Here, we demonstrate that fetal wastage triggered by prenatal Listeria monocytogenes infection is driven by placental recruitment of CXCL9-producing inflammatory neutrophils and macrophages that promote infiltration of fetal-specific T cells into the decidua. Maternal CD8+ T cells with fetal specificity upregulated expression of the chemokine receptor CXCR3 and, together with neutrophils and macrophages, were essential for L. monocytogenes-induced fetal resorption. Conversely, decidual accumulation of maternal T cells with fetal specificity and fetal wastage were extinguished by CXCR3 blockade or in CXCR3-deficient mice. Remarkably, protection against fetal wastage and in utero L. monocytogenes invasion was maintained even when CXCR3 neutralization was initiated after infection, and this protective effect extended to fetal resorption triggered by partial ablation of immune-suppressive maternal Tregs, which expand during pregnancy to sustain fetal tolerance. Together, our results indicate that functionally overriding chemokine silencing at the maternal-fetal interface promotes the pathogenesis of prenatal infection and suggest that therapeutically reinforcing this pathway represents a universal approach for mitigating immune-mediated pregnancy complications.
| S-EPMC4396484 | biostudies-literature
Project description:Microglia, the innate immune cells of the brain, plays a central role in cerebral listeriosis. Here, we present evidence that microglia control Listeria infection differently than macrophages. Infection of primary microglial cultures and murine cell lines with Listeria resulted in a dual function of the two gene expression programmes involved in early and late immune responses in macrophages. Whereas the bacterial gene hly seems responsible for both transcriptional programmes in macrophages, Listeria induces in microglia only the tumor necrosis factor (TNF)-regulated transcriptional programme. Listeria also represses in microglia the late immune response gathered in two clusters, microbial degradation, and interferon (IFN)-inducible genes. The bacterial gene actA was required in microglia to induce TNF-regulated responses and to repress the late response. Isolation of microglial phagosomes revealed a phagosomal environment unable to destroy Listeria. Microglial phagosomes were also defective in several signaling and trafficking components reported as relevant for Listeria innate immune responses. This transcriptional strategy in microglia induced high levels of TNF-? and monocyte chemotactic protein-1 and low production of other neurotoxic compounds such as nitric oxide, hydrogen peroxide, and Type I IFNs. These cytokines and toxic microglial products are also released by primary microglia, and this cytokine and chemokine cocktail display a low potential to trigger neuronal apoptosis. This overall bacterial strategy strongly suggests that microglia limit Listeria inflammation pattern exclusively through TNF-mediated responses to preserve brain integrity.
| S-EPMC4068285 | biostudies-literature