Selective cleavage of fibrinogen by diverse proteinases initiates innate allergic and antifungal immunity through CD11b

Landers, Cameron T.; Tung, H.Y. Lim; Knight, John; Madison, Matthew C.; Wu, Yifan; Zeng, Zhimin; Porter, Paul B.; Rodriguez, Antony; Flick, Matthew J.; Kheradmand, Farrah; Corry, David B.

doi:10.1074/jbc.ra118.006724

Cited by 35 publications

(46 citation statements)

References 65 publications

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“…Conformational changes in fibrinogen are able to enhance receptor interactions, for example after adsorption on surfaces, but proteolytic degradation has a role in unmasking binding sites in the D-domain to facilitate interaction with α M β 2 54,60 . For example, recent studies have proposed that full length fibrinogen interacts only weakly with α M β 2 , whereas fungal protease-derived fibrinogen cleavage products (termed 'cryptokines'), form a complex with α M β 2 and TLR4 and play a role in antifungal immune defence 60 . Whatever fibrinogen structures are binding to α M β 2 after ionomycin treatment, the details of the signalling events are not known.…”

Section: Scientific Reports |mentioning

confidence: 99%

Fibrinogen protects neutrophils from the cytotoxic effects of histones and delays neutrophil extracellular trap formation induced by ionomycin

Locke

Francis

Tsaousi

et al. 2020

Sci Rep

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neutrophils are pivotal players in immune defence which includes a process of release of histones and DnA as neutrophil extracellular traps (nets). Histones, while toxic to invading pathogens, also kill host cells, including neutrophils. Bacteria have evolved mechanisms to escape neutrophils, including the secretion of leucocidins (e.g. ionomycin). Live cell video microscopy showed how fibrinogen and fibrin influence NETosis and neutrophil responses to extracellular histones. Histones were rapidly lethal to neutrophils after binding to cells, but formation of fibrinogen/fibrin-histone aggregates prevented cell death. Histone cytotoxicity was also reduced by citrullination by peptidyl arginine deiminase 4, or digestion by serine proteases. Ionomycin and phorbol 12-myristate 13 acetate (PMA) are used to trigger netosis. fibrinogen was responsible for a second distinct mechanism of neutrophil protection after treatment with ionomycin. Fibrinogen clustered on the surface of ionomycinstimulated neutrophils to delay NETosis; and blocking the β integrin receptor, α M β 2, abolished fibrinogen protection. Fibrinogen did not bind to or protect neutrophils stimulated with PMA. fibrinogen is an acute phase protein that will protect exposed cells from damaging circulating histones or leucocidins; but fibrinogen depletion/consumption, as in trauma or sepsis will reduce protection. It is necessary to consider the role of fibrinogen in NETosis. Since the discovery of neutrophil extracellular traps (NETs) as a host defence mechanism capable of trapping and killing bacteria 1 , there has been a growing interest and research output 2. It is generally accepted that the process of generating NETs, NETosis, is a specific type of programmed cell death involving changes in the nucleus and nuclear membrane, followed by cell membrane breakdown and expulsion of DNA and associated proteins, including histones, neutrophil elastase and myeloperoxidase 3. NETs appear to generate a physical barrier and range of biochemical weapons against many pathogens, including bacteria, fungi, viruses and parasites, and are triggered by diverse pathways in the neutrophil 4. Reactive oxygen species (ROS) are implicated in NET formation and a distinction is drawn between NADPH-oxidase (NOX2) dependent and-independent mechanisms (though it is important to remember that mitochondria can also produce reactive oxygen species (ROS) in NOX2-independent NETosis 4). Common triggers used to induce neutrophils to generate NETs in vitro are phorbol 12-myristate 13 acetate (PMA) and leucocidin calcium ionophores such as ionomycin. These chemicals trigger distinct pathways 5-7 leading to the release of different families of proteins with different patterns of post translational modification 8. Whilst PMA is considered to induce typical NOX2-dependent NETosis and ionomycin-induced NETs are NOX2-independent, the relationship between NETs produced in vitro by these triggers and NETosis in vivo is unclear. Furthermore, there are many areas of disagreement and conflicting fin...

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Section: Scientific Reports |mentioning

confidence: 99%

Fibrinogen protects neutrophils from the cytotoxic effects of histones and delays neutrophil extracellular trap formation induced by ionomycin

Locke

Francis

Tsaousi

et al. 2020

Sci Rep

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“…However, when compared with the fungal species composition characterized in the present study, the fibrinogen concentration was associated with fungal diversity at company level. Apart from playing a role in the acute phase response to systemic inflammation, fibrinogen has been shown to be hydrolyzed by proteinases from Aspergillus melleus and other allergenic organisms to yield cleavage products that drive distinct antifungal mechanisms and initiates allergy (airway hypersensitivity, innate allergic inflammation and antifungal immunity) through Toll-like receptor 4 and CD11c 48 . Indeed, exposed workers had lower levels of fibrinogen compared with controls 27 , but although this may be a possible ongoing mechanism in the exposed workers, most employees in both study groups were within the reference area for fibrinogen of 1.5–4 mg mL −1 .…”

Section: Discussionmentioning

confidence: 99%

The airborne mycobiome and associations with mycotoxins and inflammatory markers in the Norwegian grain industry

Straumfors

Mundra

Foss

et al. 2021

Sci Rep

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Grain dust exposure is associated with respiratory symptoms among grain industry workers. However, the fungal assemblage that contribute to airborne grain dust has been poorly studied. We characterized the airborne fungal diversity at industrial grain- and animal feed mills, and identified differences in diversity, taxonomic compositions and community structural patterns between seasons and climatic zones. The fungal communities displayed strong variation between seasons and climatic zones, with 46% and 21% of OTUs shared between different seasons and climatic zones, respectively. The highest species richness was observed in the humid continental climate of the southeastern Norway, followed by the continental subarctic climate of the eastern inland with dryer, short summers and snowy winters, and the central coastal Norway with short growth season and lower temperature. The richness did not vary between seasons. The fungal diversity correlated with some specific mycotoxins in settled dust and with fibrinogen in the blood of exposed workers, but not with the personal exposure measurements of dust, glucans or spore counts. The study contributes to a better understanding of fungal exposures in the grain and animal feed industry. The differences in diversity suggest that the potential health effects of fungal inhalation may also be different.

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“…Previous studies have shown the expression of fibrinogen-binding proteins on the surface of conidia of A. fumigatus which promote binding to fibrinogen and host tissue [ 40 , 47 ]. The release of fungal proteases during infection has been reported to result in fibrinogen cleaving and activation of the TLR4 signaling pathway through binding of fibrinogen cleavage products [ 48 – 50 ]. The airway protease activity promoted by A. fumigatus initiates both allergic airway disease and antifungal immunity [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…The release of fungal proteases during infection has been reported to result in fibrinogen cleaving and activation of the TLR4 signaling pathway through binding of fibrinogen cleavage products [ 48 – 50 ]. The airway protease activity promoted by A. fumigatus initiates both allergic airway disease and antifungal immunity [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Proteome analysis of bronchoalveolar lavage fluids reveals host and fungal proteins highly expressed during invasive pulmonary aspergillosis in mice and humans

Machata

Lehmann

et al. 2020

Virulence

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Invasive pulmonary aspergillosis (IPA) is a severe infection that is difficult to diagnose due to the ubiquitous presence of fungal spores, the underlying diseases of risk patients, and limitations of currently available markers. In this study, we performed a comprehensive liquid chromatography tandem mass spectrometry (LC-MS/MS)-based identification of host and fungal proteins expressed during IPA in mice and humans. The proteomic analysis of bronchoalveolar lavage samples of individual IPA and control cases allowed the description of common host factors that had significantly increased abundance in both infected animals and IPA patients compared to their controls. Although increased levels of these individual host proteins might not be sufficient to distinguish bacterial from fungal infection, a combination of these markers might be beneficial to improve diagnosis. We also identified 16 fungal proteins that were specifically detected during infection and may be valuable candidates for biomarker evaluation.

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Selective cleavage of fibrinogen by diverse proteinases initiates innate allergic and antifungal immunity through CD11b

Cited by 35 publications

References 65 publications

Fibrinogen protects neutrophils from the cytotoxic effects of histones and delays neutrophil extracellular trap formation induced by ionomycin

Fibrinogen protects neutrophils from the cytotoxic effects of histones and delays neutrophil extracellular trap formation induced by ionomycin

The airborne mycobiome and associations with mycotoxins and inflammatory markers in the Norwegian grain industry

Proteome analysis of bronchoalveolar lavage fluids reveals host and fungal proteins highly expressed during invasive pulmonary aspergillosis in mice and humans

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