Global Secretome Characterization of Herpes Simplex Virus 1-Infected Human Primary Macrophages

Miettinen, Juho J.; Matikainen, Sampsa; Nyman, Tuula A.

doi:10.1128/jvi.01545-12

Cited by 44 publications

(58 citation statements)

References 47 publications

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“…Though IL-1␤ levels increased in response to infection, both in immunofluorescence assays and Western blot analysis (Fig. 1), IL-1␤ appeared as punctate cytoplasmic spots and was not secreted to detectable levels, consistent with previous reports in macrophages showing no IL-1␤ secretion during HSV-1 infection (86,87). However, these studies did not address the cytoplasmic accumulation of IL-1␤ after HSV-1 infection.…”

Section: Discussioncontrasting

confidence: 32%

Herpes Simplex Virus 1 Infection Induces Activation and Subsequent Inhibition of the IFI16 and NLRP3 Inflammasomes

Johnson

Leela

Chandran

2013

J Virol

232

294

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Inflammasomes are multiprotein complexes that recognize pathogens and pathogen-or danger-associated molecular patterns. They induce the maturation and secretion of powerful proinflammatory interleukin-1B (IL-1␤), IL-18, and IL-33 cytokines, which in turn activate expression of other immune genes and lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Inflammasomes are comprised of cytoplasmic sensor molecules, such as NLRP3 and AIM2 or nuclear sensor IFI16, the adaptor protein ASC (apoptosis-associated speck-like protein containing CARD), and the effector protein procaspase-1. Herpes simplex virus 1 (HSV-1), a ubiquitous virus that infects humans and establishes life-long latency, has evolved numerous mechanisms to evade host detection and immune responses. Here, we show that early during in vitro infection of human foreskin fibroblasts (2 to 4 h), HSV-1 induced the activation of the IFI16 and NLRP3 inflammasomes and maturation of IL-1␤. Independent of viral gene expression, IFI16 recognized the HSV-1 genome in infected cell nuclei, relocalized, and colocalized with ASC in the cytoplasm. However, HSV-1 specifically targeted IFI16 for rapid proteasomic degradation at later times postinfection, which was dependent on the expression of ICP0, an immediate early protein of HSV-1. In contrast, NLRP3, AIM2, and ASC levels were not decreased. Also, caspase-1 was "trapped" in actin clusters at later time points that likely blocked the NLRP3/IFI16 inflammasome activity. In addition, the secretion of mature IL-1␤ was inhibited. These results suggest that though the host cell responds to HSV-1 infection by IFI16 and NLRP3 inflammasomes early during infection, HSV-1 has evolved mechanisms to shut down these responses to evade the proinflammatory consequences.

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Section: Discussioncontrasting

confidence: 32%

Herpes Simplex Virus 1 Infection Induces Activation and Subsequent Inhibition of the IFI16 and NLRP3 Inflammasomes

Johnson

Leela

Chandran

2013

J Virol

232

294

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“…At present, different proteomic techniques allow for in-depth analysis of the secretome, the global pattern of secreted proteins. Secretome analysis is important in revealing complex cellular processes that require communication and signaling between the cells, and it has recently been applied to analyze the signaling pathways related to cell differentiation (19,20), cancer (21,22), and immune responses (23)(24)(25). In the present work we have characterized the secretome of human primary macrophages that have been activated simultaneously by microbial signal lipopolysaccharide (LPS) and endogenous danger signal MSU to get a global view of macrophage response to combined PAMP and DAMP stimulation.…”

Section: Monosodium Urate (Msu) Is An Endogenous Danger Signal That Imentioning

confidence: 99%

Monosodium Urate Activates Src/Pyk2/PI3 Kinase and Cathepsin Dependent Unconventional Protein Secretion From Human Primary Macrophages

Välimäki

Miettinen

Lietzén

et al. 2013

Molecular & Cellular Proteomics

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Monosodium urate (MSU) is an endogenous danger signal that is crystallized from uric acid released from injured cells. MSU is known to activate inflammatory response in macrophages but the molecular mechanisms involved have remained uncharacterized. Activated macrophages start to secrete proteins to activate immune response and to recruit other immune cells to the site of infection and/or tissue damage. Secretome characterization after activation of innate immune system is essential to unravel the details of early phases of defense responses. Here, we have analyzed the secretome of human primary macrophages stimulated with MSU using quantitative two-dimensional gel electrophoresis based proteomics as well as high-throughput qualitative GeLC-MS/MS approach combining protein separation by SDS-PAGE and protein identification by liquid chromatography-MS/MS. Both methods showed that MSU stimulation induced robust protein secretion from lipopolysaccharide-primed human macrophages. Bioinformatic analysis of the secretome data showed that MSU stimulation strongly activates unconventional, vesicle mediated protein secretion. The unconventionally secreted proteins included pro-inflammatory cytokines like IL-1␤ and IL-18, interferon-induced proteins, and danger signal proteins. Also active forms of lysosomal proteases cathepsins were secreted on MSU stimulation, and cathepsin activity was essential for MSUinduced unconventional protein secretion. Additionally, proteins associated to phosphorylation events including Src family tyrosine kinases were increased in the secretome of MSU-stimulated cells. Our functional studies demonstrated that Src, Pyk2, and PI3 kinases act upstream of cathepsins to activate the overall protein secretion from macrophages. In conclusion, we provide the first comprehensive characterization of protein secretion pathways activated by MSU in human macrophages, and reveal a novel role for cathepsins and Src, Pyk2, PI3 ki-

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“…Finally, IL-1b that has been processed is retained within HSV-1-infected cells (Fig. 4A) through an incompletely understood mechanism (129,133). Given the similarities between IL-1b and IL-18 activation (Fig.…”

Section: Viral Immune Evasion and Potential Counteraction By Il-36mentioning

confidence: 99%

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Jensen

2017

Sci. Signal.

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Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36a, IL-36b and IL-36g, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1a, IL-1b, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1a, IL-1b, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion.

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Global Secretome Characterization of Herpes Simplex Virus 1-Infected Human Primary Macrophages

Cited by 44 publications

References 47 publications

Herpes Simplex Virus 1 Infection Induces Activation and Subsequent Inhibition of the IFI16 and NLRP3 Inflammasomes

Herpes Simplex Virus 1 Infection Induces Activation and Subsequent Inhibition of the IFI16 and NLRP3 Inflammasomes

Monosodium Urate Activates Src/Pyk2/PI3 Kinase and Cathepsin Dependent Unconventional Protein Secretion From Human Primary Macrophages

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

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