The Danger Signal, Extracellular ATP, Is a Sensor for an Airborne Allergen and Triggers IL-33 Release and Innate Th2-Type Responses

Kouzaki, Hideaki; Izutsu, Koji; Kobayashi, Takao; O’Grady, Scott M.; Kita, Hirohito

doi:10.4049/jimmunol.1003020

Cited by 439 publications

(477 citation statements)

References 77 publications

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“…NH cells can produce large amounts of type-2 cytokines such as IL-5 and IL-13 in response to IL-33. Several groups have characterized populations of type-2 cytokine-producing ILCs associated with IL-33 mediate diseases in the lung [15][16][17][18][19][20][21] . However, it is unknown whether NH cells are involved in the observed corticosteroid sensitivity.…”

mentioning

confidence: 99%

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

et al. 2013

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Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NHcell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.

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confidence: 99%

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

et al. 2013

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“…IL-33 is released from epithelial cells on exposure to allergens and is crucial for the process of allergic sensitization (21,22). IL-33 recruits type 2 innate lymphoid cells (ILC2s), which express the transcription factor GATA3 and produce IL-13 and IL-5, much like helper T type 2 cells (23,24).…”

mentioning

confidence: 99%

Apoptosis and Engulfment by Bronchial Epithelial Cells. Implications for Allergic Airway Inflammation

Penberthy

Juncadella²,

Ravichandran³

2014

Annals ATS

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Insult or injury to the lung epithelial cells from pathogens, pollutants, and allergens can initiate the process of apoptotic cell death. Although "Creola bodies," which are clusters of uncleared, apoptotic, epithelial cells, have been seen in the sputum of patients with asthma, the clearance of these dying epithelial cells and the consequence of failed clearance in the airway have not been directly addressed. We have observed that bronchial epithelial cells efficiently engulf their apoptotic neighbors and produce antiinflammatory cytokines when engulfing apoptotic cells. Furthermore, when the phagocytic capacity of bronchial epithelial cells was impaired, mice developed severe, IL-33-dependent, allergic airway inflammation. This inflammation could be ameliorated by exogenous administration of the antiinflammatory cytokine IL-10. Our data suggest that the process of apoptotic cell engulfment is a mechanism by which bronchial epithelial cells regulate the inflammatory environment within the lung. Collectively, these studies suggest that impaired engulfment pathways in airway epithelial cells can contribute to allergic airway inflammation and that targeting these pathways may be of benefit in human airway inflammation.

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“…In addition, when the cells were exposed to HDM, IL-25 protein was detected predominantly in the cytoplasm ( Figure 3B). Endogenous ATP and engagement of purinergic receptors plays a pivotal role in IL-33 release by NHBE cells (25). Extracellular release of IL-25 protein was also partially but significantly inhibited by global antagonists for purinergic receptors, including oxidized ATP and suramin ( Figure 3C).…”

Section: Il-25 Is Actively and Rapidly Released Without Apparent Cellmentioning

confidence: 93%

“…In a previous study, we found that an IL-1-family cytokine, IL-33, is constitutively produced and stored in nuclei of NHBE cells. Extracts of certain allergens, but not LPS, stimulated extracellular release of this stored IL-33 (25). Therefore, we suspected that IL-25 might be regulated similarly to IL-33.…”

Section: Il-25 Protein Is Detectable In Resting Aecsmentioning

confidence: 94%

Transcription of Interleukin-25 and Extracellular Release of the Protein Is Regulated by Allergen Proteases in Airway Epithelial CELLS

Kouzaki

Tojima

Kita

et al. 2013

Journal of Allergy and Clinical Immunology

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Epithelial cells at mucosal surfaces are integral components of innate and adaptive immunity. IL-25 is reportedly produced by epithelial cells and likely plays vital roles in regulating type-2 immune responses. However, little is known regarding the mechanisms that control production and extracellular releases of IL-25. We hypothesized that proteases from the multiple allergens may induce IL-25 production in airway epithelial cells. In this study, we found that IL-25 is constitutively produced and detectable in cytoplasm of resting normal human bronchial epithelial (NHBE) cells. When exposed to airborne allergens such as house dust mite (HDM), stored IL-25 was released rapidly to the extracellular space. IL-25 release was not accompanied by cell death, suggesting involvement of active secretory mechanism(s). HDM also enhanced IL-25 mRNA transcription, which was dependent on their protease activities. Furthermore, activation of NHBE cells with authentic proteases, such as trypsin and papain, or with a peptide agonist for protease-activated receptor 2 was sufficient to enhance IL-25 mRNA transcription and protein. Protease-driven increase in mRNA transcription and allergen-driven extracellular release of IL-25 protein was also observed in primary nasal epithelial cells from healthy individuals. These findings suggest that IL-25 production by airway epithelial cells is regulated by the transcription and protein release levels and that allergen proteases likely play pivotal roles in both biological processes.Keywords: airway epithelial cells; allergen; PAR-2; protease; In addition to being a physical barrier between the airway and the immune system, epithelial cells are now thought to play vital roles in innate and adaptive immune responses (1). Epithelial cells produce chemokines and cytokines that recruit and enhance survival of dendritic cells and interact directly with dendritic cells through membrane-associated chemokines (2-4). Epithelial cells also express soluble and cell-surface molecules that regulate recruitment, differentiation, proliferation, and function of T and B cells (2, 5). In particular, newly discovered epithelial-derived cytokines, such as thymic stromal lymphopoietin, IL-25, and IL-33, may play key roles in the development and regulation of T helper 2 (Th2) cytokine-dependent immune responses (6).There is increasing evidence to suggest the roles for IL-25 in the type-2 immune response and in the pathogenesis of asthma and allergic diseases. IL-25 (also known as IL-17E) is a member of a family of six structurally related but functionally distinct proteins. IL-17A and IL-17F appear to play important roles in neutrophilic inflammation and autoimmunity. In contrast, IL-25 is exceptional in promoting eosinophilic inflammation and a type-2 immune response (7). This has been well demonstrated in mouse models: exogenous administration of IL-25 (8, 9) or transgenic expression (10, 11) induces Th2-type inflammation. IL-25 is increased in animal bronchial challenge models (12), and its inhibition reduce...

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The Danger Signal, Extracellular ATP, Is a Sensor for an Airborne Allergen and Triggers IL-33 Release and Innate Th2-Type Responses

Cited by 439 publications

References 77 publications

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

Apoptosis and Engulfment by Bronchial Epithelial Cells. Implications for Allergic Airway Inflammation

Transcription of Interleukin-25 and Extracellular Release of the Protein Is Regulated by Allergen Proteases in Airway Epithelial CELLS

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