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Expression arrays of inflammatory Ly6C+ monocytes in mice primary or secondary challenged with Listeria monocytogenes

ABSTRACT: In this study we investigated the mechanisms involved in memory T-cell mediated protection using mice vaccinated with the intracellular bacterium Listeria monocytogenes. Our working hypothesis was that rapid activation of cells of the innate immune system, in particular inflammatory Ly6C+ monocytes, were essential in effective protection, in a memory T cell-dependent manner. Thus we generated a comprehensive comparison of the genetic program of activated Ly6C+ monocytes during a primary or a secondary infection with Listeria monocytogenes, at 8 hours post challenge infection. Abstract of corresponding publication: Cells of the innate immune system are essential for host defenses against primary microbial pathogen infections, yet their involvement in effective memory responses of vaccinated individuals has been poorly investigated. Here we show that memory T cells instruct innate cells to become potent effector cells in a systemic and a mucosal model of infection. Memory T cells controlled phagocyte, dendritic cell and NK or NK T cell mobilization and induction of a strong program of differentiation, which included their expression of effector cytokines and microbicidal pathways, all of which were delayed in non-vaccinated hosts. Disruption of IFN-gamma-signaling in Ly6C+ monocytes, dendritic cells and macrophages impaired these processes and the control of pathogen growth. These results reveal how memory T cells, through rapid secretion of IFN-gamma, orchestrate extensive modifications of host innate immune responses that are essential for effective protection of vaccinated hosts.

ORGANISM(S): Mus musculus

PROVIDER: GSE58014 | GEO | 2015/06/04

SECONDARY ACCESSION(S): PRJNA248714

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 (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.

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.

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Expression arrays of inflammatory Ly6C+ monocytes in mice primary or secondary challenged with Listeria monocytogenes

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