Trichothecene mycotoxins activate NLRP3 inflammasome through a P2X7 receptor and Src tyrosine kinase dependent pathway

Kankkunen, Päivi; Välimäki, Elina; Rintahaka, Johanna; Palomäki, Jaana; Nyman, Tuula A.; Alenius, Harri; Wolff, Henrik; Matikainen, Sampsa

doi:10.1016/j.humimm.2013.11.010

Cited by 33 publications

(23 citation statements)

References 38 publications

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“…In many previous in vitro studies, much higher LPS concentrations have been used, typically 100 or 1000 ng/ml. In these studies, co-exposure to mycotoxins and LPS either reduced the cytokine production (at 100 ng/ml) (Johannessen et al, 2009) or in most studies increased it, sometimes synergistically (Gammelsrud et al, 2012;Islam and Pestka, 2006;Kankkunen et al, 2009Kankkunen et al, , 2014; Zhou et al, 1999). The immune responses to LPS can vary between species (Munford, 2010) and depend on the dose (Morris and Li, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, microbial cell wall components, such as the fungal polysaccharide b-glucan and bacterial lipopolysaccharide (LPS), are ubiquitous and potent inducers of inflammatory responses. Some synergistic interactions between trichothecene mycotoxins and LPS have been shown in human macrophages (Kankkunen et al, 2009(Kankkunen et al, , 2014 and mouse nasal airways (Islam et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Synergistic proinflammatory interactions of microbial toxins and structural components characteristic to moisture-damaged buildings

et al. 2016

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Indoor exposure to microbes and their structural and metabolic compounds is notoriously complex. To study proinflammatory interactions between the multiple microbial agents, macrophages derived from human THP-1 monocytic cells were exposed to several concentrations of microbial toxins alone (emodin, enniatin B, physcion, sterigmatocystin, valinomycin) and in combination with microbial structural components (bacterial lipopolysaccharide [LPS] or fungal b-glucan). While the expression of proinflammatory cytokines TNFa and IL-1b to single toxins alone was modest, low-dose co-exposure with structural components increased the responses of emodin, enniatin B, and valinomycin synergistically, both at the mRNA and protein level, as measured by RT-qPCR and ELISA, respectively. Co-exposure of toxins and b-glucan resulted in consistent synergistically increased expression of several inflammation-related genes, while some of the responses with LPS were also inhibitory. Co-exposure of toxins with either b-glucan or LPS induced also mitochondrial damage and autophagocytosis. The results demonstrate that microbial toxins together with bacterial and fungal structural components characteristic to moisture-damaged buildings can have drastic synergistic proinflammatory interactions at low exposure levels. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Received for review 8 September 2015. Accepted for publication 18 January 2016. Practical ImplicationsIn this study, we evaluated joint effects between indoor microbial toxins and structural components of bacteria and fungi commonly found in moisture-damaged buildings, using human macrophages. We show here that microbial toxins can potentiate the inflammatory effects of structural components at very low exposure levels drastically increasing the severity of proinflammatory responses. Co-effects are accompanied by morphological alterations indicative of mitochondrial damage and autophagy-related activation pathways. The synergistic nature of interactions may help in understanding the adverse health effects observed in occupants of moisture-damaged buildings.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synergistic proinflammatory interactions of microbial toxins and structural components characteristic to moisture-damaged buildings

et al. 2016

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“…Src kinase plays an important role in the regulation of immunity and the inflammatory response [8,9]. Bacterial or viral pathogens have been shown to cause a Src kinase mediated activation of the NLR3 inflammasome [25]. Interestingly, Src kinase mediated autophagy has been linked to E3 ubiquitin ligase (c-Cbl), which has been shown to provide a negative feedback to the production of Src kinase.…”

Section: Discussionmentioning

confidence: 99%

The Role of Src Kinase in the Caspase-1 Pathway After Hypoxia in the Brain of Newborn Piglets

Angelis

Fontánez-Nieves

Delivoria‐Papadopoulos

2014

Neurochem Res

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Hypoxia induces a cerebral inflammatory response, which contributes to brain injury. Inflammasomes are complex intracellular molecular structures that initiate the inflammatory cascade. Caspase-1 and interleukin 1-β (IL-1β), have been established as markers of inflammasome activation. Src kinase, a cytosolic non-receptor protein tyrosine kinase, is linked to cell proliferation and differentiation and is up regulated during hypoxia. The role of Src kinase in the above pathway is not fully understood. The present study tests the hypothesis that inhibition of Src kinase, by a selective inhibitor, PP2, will prevent the activation of caspase-1 and production of IL-1β acutely, as well as at 1 and 15 days after hypoxia in the cerebral cortex of the newborn piglet. Piglets were divided into: Normoxia (Nx), Hypoxia acute (Hx), Hypoxia-day 1 (Hx-day 1), and Hypoxia day 15 (Hx-day 15). Piglets pretreated with Src kinase inhibitor, PP2, 1 mg/kg IV, 30 min prior to hypoxia were divided into: Hypoxia acute (Hx + PP2), 1 day (Hx + PP2-day 1), and day 15 (Hx + PP2-day 15). Hypoxia was induced by exposing the piglets to an FiO2 of 0.07 for 1 hour. Caspase-1 activity and expression were determined with spectrophotometry and Western blot respectively, while IL-1β levels were measured by solid phase ELISA. Caspase-1 activation was achieved immediately (within 1 h) after hypoxia and persisted for 15 days. IL-1β level was also increased after hypoxia reaching a maximum level at 24 h following hypoxia and returned to baseline by 15 days. Administration of PP2 attenuated the activity acutely, but not the expression of the caspase-1. IL-1β level at 24 h after hypoxia returned to baseline in piglets that were pretreated with PP2. We provide evidence that inhibition of Src kinase in the acute phase after hypoxia involves changes in the production or processing of caspase-1 subunits. Our data suggest that Src kinase mediates hypoxia-induced caspase-1 activation in the cerebral cortex of newborn piglets. Inhibition of Src kinase may attenuate the neuroinflammatory response and could represent a potential target for neuroprotection after hypoxic injury.

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“…The inflammasomes detect intracellular or extracellular danger signals, become activated, and trigger cysteine protease caspase-1-dependent processing of the proinflammatory cytokine IL-1 β in the macrophage. Bacterial or viral pathogens can activate the NLR3 inflammasome/caspase-1/IL-1 β pathway via Src kinase-mediated mechanisms [10]. Src kinase has been also shown to affect caspase-1 activity in hippocampal neurons derived from mice.…”

Section: Introductionmentioning

confidence: 99%

Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model

Angelis

Delivoria‐Papadopoulos

2017

Mediators of Inflammation

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Background Protein tyrosine phosphatases (PTPs) in conjunction with protein tyrosine kinases (PTKs) regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B) is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks. Methods Newborn piglets were divided into groups: normoxia, hypoxia, hypoxia followed by 1 day and 15 days in FiO2 0.21, and hypoxia pretreated with Src kinase inhibitor PP2, prior to hypoxia followed by 1 day and 15 days. Hypoxia was achieved by providing 7% FiO2 for 1 hour and PTP-1B expression was measured via immunoblotting. Results PTP-1B increased posthypoxia by about 30% and persisted for 2 weeks while Src kinase inhibition attenuated the expected PTP-1B-increased expression. Conclusions Our study suggests that Src kinase mediates a hypoxia-induced increased PTP-1B expression.

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Trichothecene mycotoxins activate NLRP3 inflammasome through a P2X7 receptor and Src tyrosine kinase dependent pathway

Cited by 33 publications

References 38 publications

Synergistic proinflammatory interactions of microbial toxins and structural components characteristic to moisture-damaged buildings

Synergistic proinflammatory interactions of microbial toxins and structural components characteristic to moisture-damaged buildings

The Role of Src Kinase in the Caspase-1 Pathway After Hypoxia in the Brain of Newborn Piglets

Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model

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