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Arginine utilization following mycobacteria infection in macrophages is dependent on autocrine-paracrine signaling

ABSTRACT: Nitric oxide (NO) produced by macrophages (MØs) is toxic to both host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. MØ arginase 1 (Arg1) inhibits NO production by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control Arg1 expression in MØs. First, a MyD88-dependent pathway induces Arg1 in intracellular infections, while a second Stat6-dependent pathway is required for Arg1 expression in alternativelyactivated MØs. We found that mycobacteria-infected MØs produce soluble factors that induce Arg1 in an autocrine-paracrine manner via Stat3. We identify these factors as IL-6, IL-10 and GCSF. We further establish that Arg1 expression is controlled by the MyD88-dependent production of IL-6, IL-10 and G-CSF rather than cell intrinsic MyD88 signaling to Arg1. Our data reveal the MyD88-dependent pathway of Arg1induction following BCG infection requires Stat3 activation and may result in the development of an immunosuppressive niche in granulomas due to the induced Arg1 production in surrounding uninfected MØs

ORGANISM(S): Mus musculus

PROVIDER: GSE22935 | GEO | 2010/07/14

SECONDARY ACCESSION(S): PRJNA127939

REPOSITORIES: GEO

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Arginine utilization following mycobacteria infection in macrophages is dependent on autocrine-paracrine signaling

Project description:Nitric oxide (NO) produced by macrophages (MØs) is toxic to both host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. MØ arginase 1 (Arg1) inhibits NO production by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control Arg1 expression in MØs. First, a MyD88-dependent pathway induces Arg1 in intracellular infections, while a second Stat6-dependent pathway is required for Arg1 expression in alternativelyactivated MØs. We found that mycobacteria-infected MØs produce soluble factors that induce Arg1 in an autocrine-paracrine manner via Stat3. We identify these factors as IL-6, IL-10 and GCSF. We further establish that Arg1 expression is controlled by the MyD88-dependent production of IL-6, IL-10 and G-CSF rather than cell intrinsic MyD88 signaling to Arg1. Our data reveal the MyD88-dependent pathway of Arg1induction following BCG infection requires Stat3 activation and may result in the development of an immunosuppressive niche in granulomas due to the induced Arg1 production in surrounding uninfected MØs We used microarrays to perform genome wide expression analysis in mycobacteria-infected macrophages from C57Bl/6 WT and MyD88-knockout mice.

2010-07-14 | E-GEOD-22935 | biostudies-arrayexpress

IL-21-mediated non-canonical pathway for IL-1? production in conventional dendritic cells

Project description:The canonical pathway for IL-1? production requires TLR-mediated NF-?B-dependent Il1b gene induction, followed by caspase-containing inflammasome-mediated processing of pro-IL-1?. Here we show that IL-21 unexpectedly induces IL-1? production in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-?B-independent pathway. IL-21 does not induce Il1b expression in CD4+ T cells, with differential histone marks present in these cells versus cDCs. IL-21-induced IL-1? processing in cDCs does not require caspase-1 or caspase-8 but depends on IL-21-mediated death and activation of serine protease(s). Moreover, STAT3-dependent IL-1? expression in cDCs at least partially explains the IL-21-mediated pathologic response occurring during infection with Pneumonia Virus of Mice. These results demonstrate lineage-restricted IL-21-induced IL-1? via a non-canonical pathway and provide evidence for its importance in vivo. Genome-wide transcription factors mapping and binding of STAT3, H3K4me3, H3K27me, H3K4me1, H3K27ac in mouse CD4+ T cells and dendritic cells in WT and Stat3-/- mice. RNA-Seq is performed in mouse CD4+ T cells and dendritic cells in WT mice, with or without indicated cytokines.

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Identify the downstream targets of Stat3 by using an engineered mouse ES cell line treated with GCSF and LIF plus PD0325901

2012-06-14 | GSE38719 | GEO

CIS deficiency intensifies GM-CSF signaling to polarize alternative activated macrophages

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2023-01-21 | PXD018390 | Pride

IL-21-mediated non-canonical pathway for IL-1β production in conventional dendritic cells

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Khandibharad2022 - IL-12 regulation by IL-10 in Leishmaniasis

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2022-01-24 | MODEL2012040002 | BioModels

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