Streptolysin O Induces the Ubiquitination and Degradation of Pro-IL-1β

Hancz, Dóra; Westerlund, Elsa; Valfridsson, Christine; Aemero, Getachew Melkamu; Bastiat-Sempe, Benedicte; Orning, Pontus; Lien, Egil; Wessels, Michael R.; Persson, Jenny

doi:10.1159/000496403

Cited by 19 publications

(20 citation statements)

References 56 publications

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“…In addition, the amount of IL-1 β in the medium of all groups was so small that there was no significant difference between them ( Figure 2(f) ). Some bacterial metabolites can result in the ubiquitination and degradation of the inactive proform before mature IL-1 β is produced [ 44 ]. This can be a probable explanation of this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

Wang

Gao

et al. 2020

BioMed Research International

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Background. The brain is in many ways an immunologically and pharmacologically privileged site because of the blood-brain barrier (BBB). But for chronic peripheral inflammation, inflammatory signals can be transmitted from the peripheral system into the central nervous system (CNS) through multiple channels and result in neuroinflammation. Leptomeningeal cells that form the BBB can trigger one signaling pathway by releasing cytokines to transmit inflammatory signals. Besides, the Janus kinase (JAK) family may have a certain function in the activation of leptomeninges. In the present study, we try to use coniferyl aldehyde (CA), a natural anti-inflammatory phenolic compound, to inhibit this inflammatory process and elucidate the underlying molecular mechanisms. Results. Secretion of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) significantly increased after incubation with P. gingivalis. Moreover, TNF-α, IL-1β, and IL-6 levels were upregulated, and the JAK2 signaling was enhanced in leptomeningeal cells in a conditioned medium from activated macrophages, which leads to the immune response in microglia. However, this inflammatory effect of leptomeningeal cells was reversed by CA administration, accompanied by the decreased immune response in microglia. The western blot assay revealed that JAK2 phosphorylation was suppressed in leptomeningeal cells treated with CA. Conclusions. This study demonstrates that activated macrophages by P. gingivalis markedly induce the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) from leptomeningeal cells, thereby activating the JAK2 signaling pathway and subsequently enhancing immune responses in microglia in the CNS. CA effectively inhibits the inflammatory effect of leptomeningeal cells via suppressing the JAK2 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

Wang

Gao

et al. 2020

BioMed Research International

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“…For example, SLO induces host degradation of IL-1 via ubiquitination, and SpyCEP directly degrades IL-8 via proteolytic cleavage. 33,34 Here, we describe a distinct mechanism of suppression upstream of these pathways. Interestingly, the strain MGAS315 was the only strain tested which failed to suppress macrophage cytokine responses (Fig 1E).…”

Section: Discussionmentioning

confidence: 99%

AStreptococcusquorum sensing system enables suppression of innate immunity

Rahbari

Chang

Federle

2020

Preprint

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Some bacterial pathogens utilize cell-cell communication systems, such as quorum sensing (QS), to coordinate genetic programs during host colonization and infection. The human-restricted pathosymbiont Streptococcus pyogenes (Group A Streptococcus, GAS) uses the Rgg2/Rgg3 QS system to modify the bacterial surface, enabling biofilm formation and lysozyme resistance. Here, we demonstrate that innate immune cell responses to GAS are substantially altered by the QS status of the bacteria. We found that macrophage activation, stimulated by multiple agonists and assessed by cytokine production and NFκB activity, was substantially suppressed upon interaction with QS-active GAS but not QS-inactive bacteria. Neither macrophage viability nor bacterial adherence were seen as different between QS activity states, yet TNFα, IL-6, and IFNβ levels and NFκB reporter activity were drastically lower following infection with QS-active GAS. Suppression required contact between viable bacteria and macrophages. A QS-regulated biosynthetic gene cluster (BGC) in the GAS genome, encoding several putative enzymes, was also required for macrophage modulation. Our findings suggest a model wherein upon contact with macrophages, QS-active GAS produce a BGC-derived factor capable of suppressing inflammatory responses. The suppressive capability of QS-active GAS is abolished after treatment with a specific QS inhibitor. These observations suggest that interfering with the ability of bacteria to collaborate via QS can serve as a strategy to counteract microbial efforts to manipulate host defenses.ImportanceStreptococcus pyogenes is restricted to human hosts and commonly causes superficial diseases such as pharyngitis; it can also cause severe and deadly manifestations including necrotizing skin disease or severe post-infectious sequelae like rheumatic heart disease. Understanding the complex mechanisms used by this pathogen to manipulate host defenses could aid in developing new therapeutics to treat infections. Here, we examine the impact of a bacterial cell-cell communication system, which is highly conserved across S. pyogenes, on host innate immune responses. We find that S. pyogenes uses this system to suppress macrophage pro-inflammatory cytokine responses. Interference with this communication system could serve as a strategy to disarm bacteria and maintain an effective immune response.

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“…The ability of PTMs to regulate inflammasome activation has also been exploited by pathogens, for example, the bacterial toxin Streptolysin O induces ubiquitination and degradation of pro‐IL‐1β, therefore playing an important role in bacterial virulence and pathogenesis by limiting availability of pro‐IL‐1β and subsequently reducing the amount of mature IL‐1β released from Mϕs in response to infection 75 . In another example, stimulation of THP‐1 cells with Helicobacter pylori LPS triggers activation of PI‐3K/Rac1/p21‐activated kinase 1 (PAK1).…”

Section: Ptms Of Caspase‐1 and Pro‐il‐1βmentioning

confidence: 99%

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

McKee

Coll

2020

Journal of Leukocyte Biology

138

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The NLRP3 (NOD‐, LRR‐, and pyrin domain‐containing protein 3) inflammasome is an immunological sensor that detects a wide range of microbial‐ and host‐derived signals. Inflammasome activation results in the release of the potent pro‐inflammatory cytokines IL‐1β and IL‐18 and triggers a form of inflammatory cell death known as pyroptosis. Excessive NLRP3 activity is associated with the pathogenesis of a wide range of inflammatory diseases, thus NLRP3 activation mechanisms are an area of intensive research. NLRP3 inflammasome activation is a tightly regulated process that requires both priming and activation signals. In particular, recent research has highlighted the highly complex nature of the priming step, which involves transcriptional and posttranslational mechanisms, and numerous protein binding partners. This review will describe the current understanding of NLRP3 priming and will discuss the potential opportunities for targeting this process therapeutically to treat NLRP3‐associated diseases.

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Streptolysin O Induces the Ubiquitination and Degradation of Pro-IL-1β

Cited by 19 publications

References 56 publications

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

AStreptococcusquorum sensing system enables suppression of innate immunity

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

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