Trichothecene Mycotoxins Activate Inflammatory Response in Human Macrophages

Kankkunen, Päivi; Rintahaka, Johanna; Aalto, Annika; Leino, Marina; Majuri, Marja‐Leena; Alenius, Harri; Wolff, Henrik; Matikainen, Sampsa

doi:10.4049/jimmunol.0803309

Cited by 75 publications

(53 citation statements)

References 69 publications

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“…The repeatedly exposed mice had decreased levels of TNF-a, which is associated with a type 1 immune response, and increased levels of eosinophils and IL-4, IL-5, and IL-13, which are associated with a type 2 immune response (32), compared with the singledosed mice. The inflammation was probably mediated in part by S. chartarum mycotoxins, such as satratoxin G, roridin A, verrucarin A, and T-2 toxin (33,34), and chitins in the outer wall of the spores. Chitins and b-glucans have been reported to induce a type 2 immune response (35).…”

Section: Discussionmentioning

confidence: 99%

Repeated Mouse Lung Exposures toStachybotrys chartarumShift Immune Response from Type 1 to Type 2

Lichtenstein¹,

Molina²,

Donaghey³

et al. 2016

Am J Respir Cell Mol Biol

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After a single or multiple intratracheal instillations of Stachybotrys chartarum (S. chartarum or black mold) spores in BALB/c mice, we characterized cytokine production, metabolites, and inflammatory patterns by analyzing mouse bronchoalveolar lavage (BAL), lung tissue, and plasma. We found marked differences in BAL cell counts, especially large increases in lymphocytes and eosinophils in multipledosed mice. Formation of eosinophil-rich granulomas and airway goblet cell metaplasia were prevalent in the lungs of multiple-dosed mice but not in single-or saline-dosed groups. We detected changes in the cytokine expression profiles in both the BAL and plasma. Multiple pulmonary exposures to S. chartarum induced significant metabolic changes in the lungs but not in the plasma. These changes suggest a shift from type 1 inflammation after an acute exposure to type 2 inflammation after multiple exposures to S. chartarum. Eotaxin, vascular endothelial growth factor (VEGF), MIP-1a, MIP-1b, TNF-a, and the IL-8 analogs macrophage inflammatory protein-2 (MIP-2) and keratinocyte chemoattractant (KC), had more dramatic changes in multiplethan in single-dosed mice, and parallel the cytokines that characterize humans with histories of mold exposures versus unexposed control subjects. This repeated exposure model allows us to more realistically characterize responses to mold, such as cytokine, metabolic, and cellular changes.

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Section: Discussionmentioning

confidence: 99%

Repeated Mouse Lung Exposures toStachybotrys chartarumShift Immune Response from Type 1 to Type 2

Lichtenstein¹,

Molina²,

Donaghey³

et al. 2016

Am J Respir Cell Mol Biol

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show abstract

“…The primer and probe sets were designed and optimized according to Applied Biosystems guidelines. Quantification was performed by using the comparative DDC T method as previously described (29). Real-time PCR data were developed by using the Sequence detector system version 1.4 software (Applied Biosystems) and the analyzed results were finally expressed as relative units.…”

Section: Quantitative Real-time Rt-pcr Assay and Data Analysismentioning

confidence: 99%

(1,3)-β-Glucans Activate Both Dectin-1 and NLRP3 Inflammasome in Human Macrophages

Kankkunen

Teirilä

Rintahaka

et al. 2010

The Journal of Immunology

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243

210

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β-glucans are naturally occurring polysaccharides that are the major cell wall components of fungi. Recognition of β-glucans is mediated through a membrane-bound pattern recognition receptor called dectin-1, and gene knock-out studies have shown that dectin-1 plays an important role in antifungal immune response in vivo. In this report, we have studied the effect of large particulate (1,3)-β-glucans, including curdlan, glucan from baker's yeast, paramylon, and zymosan, on inflammatory response in human macrophages. We show that β-glucans activate the transcription of the proinflammatory cytokine IL-1β through a dectin-1–dependent pathway in human macrophages. Moreover, dectin-1 receptor associated Syk tyrosine kinase was essential for β-glucan induced IL-1β mRNA expression. In contrast to LPS, β-glucans also strongly activated the secretion of IL-1β. This β-glucan triggered IL-1β release was abolished by cytochalasin D, an inhibitor of phagocytosis, demonstrating that cytosolic recognition of β-glucans is required for IL-1β response in human macrophages. RNA interference-mediated gene knockdown experiments demonstrated that cytoplasmic NLRP3 inflammasome is essential for β-glucan–induced IL-1β secretion. Moreover, our results suggest that β-glucan–induced NLRP3 inflammasome activation is dependent on the dectin-1/Syk signaling pathway. Furthermore, our results suggest that the lysosomal cathepsin B protease, the formation of reactive oxygen species, and the efflux of potassium are needed for β-glucan–induced NLRP3 inflammasome activation. In conclusion, our results show that β-glucans are recognized by membrane-associated dectin-1 and cytoplasmic NLRP3 inflammasome resulting in IL-1β gene transcription and IL-1β secretion in human macrophages, respectively.

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“…The DAMPs include, for example, extracellular ATP and crystalline monosodium urate (19,20). In addition to these endogenous stimuli, NLRP3-inflammasome is activated by exogenous stimuli, including asbestos, silica, aluminum adjuvant (21,22), fungal toxins (23), b-glucans (24), and viral infections (25)(26)(27). Because these activators are chemically and structurally different, they probably are indirectly recognized by the NLRP3-inflammasome.…”

mentioning

confidence: 99%

Recognition of Cytoplasmic RNA Results in Cathepsin-Dependent Inflammasome Activation and Apoptosis in Human Macrophages

Rintahaka

Lietzén

Öhman

et al. 2011

The Journal of Immunology

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dsRNA is an important pathogen-associated molecular pattern that is primarily recognized by cytosolic pattern-recognition receptors of the innate-immune system during virus infection. This recognition results in the activation of inflammasome-associated caspase-1 and apoptosis of infected cells. In this study, we used high-throughput proteomics to identify secretome, the global pattern of secreted proteins, in human primary macrophages that had been activated through the cytoplasmic dsRNA-recognition pathway. The secretome analysis revealed cytoplasmic dsRNA-recognition pathway-induced secretion of several exosome-associated proteins, as well as basal and dsRNA-activated secretion of lysosomal protease cathepsins and cysteine protease inhibitors (cystatins). Inflammasome activation was almost completely abolished by cathepsin inhibitors in response to dsRNA stimulation, as well as encephalomyocarditis virus and vesicular stomatitis virus infections. Interestingly, Western blot analysis showed that the mature form of cathepsin D, but not cathepsin B, was secreted simultaneously with IL-18 and inflammasome components ASC and caspase-1 in cytoplasmic dsRNA-stimulated cells. Furthermore, small interfering RNA-mediated silencing experiments confirmed that cathepsin D has a role in inflammasome activation. Caspase-1 activation was followed by proteolytic processing of caspase-3, indicating that inflammasome activation precedes apoptosis in macrophages that had recognized cytoplasmic RNA. Like inflammasome activation, apoptosis triggered by dsRNA stimulation and virus infection was effectively blocked by cathepsin inhibition. In conclusion, our results emphasize the importance of cathepsins in the innate immune response to virus infection.

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Trichothecene Mycotoxins Activate Inflammatory Response in Human Macrophages

Cited by 75 publications

References 69 publications

Repeated Mouse Lung Exposures toStachybotrys chartarumShift Immune Response from Type 1 to Type 2

Repeated Mouse Lung Exposures toStachybotrys chartarumShift Immune Response from Type 1 to Type 2

(1,3)-β-Glucans Activate Both Dectin-1 and NLRP3 Inflammasome in Human Macrophages

Recognition of Cytoplasmic RNA Results in Cathepsin-Dependent Inflammasome Activation and Apoptosis in Human Macrophages

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