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Mast cells in response to some pathogens elicit a transcriptional program devoid of type I IFN response

ABSTRACT: Although mast cells elicit proinflammatory and type I IFN responses upon VSV infection, in response to L.monocytogenes (L.m) or S. Typhimurium (S.t), such cells elicit a transcriptional program devoid of type I IFN response. Balanced induction of proinflamatory and type I interferon (IFN) responses upon activation of Toll like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmune syndromes. However, their potential role in anti-microbial host defenses is increasingly being acknowledged. How mast cells interact with microbes and the nature of responses triggered thereof is not well characterized. Here we show that in response to TLR activation by Gram-positive and negative bacteria or their components like LPS, unlike macrophages, mast cells elicit pro-inflammatory but not type I IFN responses. We demonstrate that in mast cells, the bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization - a prerequisite for type I IFN induction. Such cells could, however, elicit type I IFNs in response to vesicular stomatitis virus (VSV), which accesses the cytosolic RIG-I receptor. Although important for anti-viral immunity, a strong type I IFN response is known to contribute to pathogenesis during bacterial infection. Thus, while endowed with the capacity to elicit type I IFNs in response to viral infection, the fact that mast cells only elicit pro-inflammatory responses upon bacterial infection illustrates that mast cells, key effector cells of the innate immune system, are well adjusted for optimal anti-bacterial and anti-viral responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE18500 | GEO | 2009/12/31

SECONDARY ACCESSION(S): PRJNA120249

REPOSITORIES: GEO

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Project description:Although mast cells elicit proinflammatory and type I IFN responses upon VSV infection, in response to L.monocytogenes (L.m) or S. Typhimurium (S.t), such cells elicit a transcriptional program devoid of type I IFN response. Balanced induction of proinflamatory and type I interferon (IFN) responses upon activation of Toll like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmune syndromes. However, their potential role in anti-microbial host defenses is increasingly being acknowledged. How mast cells interact with microbes and the nature of responses triggered thereof is not well characterized. Here we show that in response to TLR activation by Gram-positive and negative bacteria or their components like LPS, unlike macrophages, mast cells elicit pro-inflammatory but not type I IFN responses. We demonstrate that in mast cells, the bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization - a prerequisite for type I IFN induction. Such cells could, however, elicit type I IFNs in response to vesicular stomatitis virus (VSV), which accesses the cytosolic RIG-I receptor. Although important for anti-viral immunity, a strong type I IFN response is known to contribute to pathogenesis during bacterial infection. Thus, while endowed with the capacity to elicit type I IFNs in response to viral infection, the fact that mast cells only elicit pro-inflammatory responses upon bacterial infection illustrates that mast cells, key effector cells of the innate immune system, are well adjusted for optimal anti-bacterial and anti-viral responses. Wild type control (cntr) or interferon receptor (IFNAR)-deficient mast cells (MC) or macrophages (MAC) were infected with L.m. and S.t. (MOIs 50 and 5 for MC and MAC, respectively). MC and MAC were exposed to VSV-AV2 (MOI: 2). Samples were analyzed after 6 hours. Uninfected/unstimulated cells were used as reference samples for calculating fold change in gene expression. Gene Expression levels were determined by the Affymetrix MOE 430 2.0 GeneChips. Signal Intensities were calculated using the RMA algorithm and for statistical analysis we applied GeneSpring GX 10 software suite (Agilent Technologies, Waldbronn, Germany). MultiExperiment Viewer (MEV) software version 4.4 of the Institute for Genomic Research was used for clustering algorithm data analysis and visualization.

Project description:Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive T cell immunity.

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Mast cells in response to some pathogens elicit a transcriptional program devoid of type I IFN response

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