A Protease-Activated Pathway Underlying Th Cell Type 2 Activation and Allergic Lung Disease

Kheradmand, Farrah; Kiss, Attila; Xu, Jie; Lee, Seung‐Hyo; Kolattukudy, Pappachan E.; Corry, David B.

doi:10.4049/jimmunol.169.10.5904

Cited by 290 publications

(315 citation statements)

References 78 publications

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“…Live A. fumigatus was also shown to downregulate the proinflammatory function of mouse airway DCs exposed to mite allergens (67). In contrast, other studies rather suggested that ASP treatment leads to partially matured DCs, driving a Th2 cell polarization with IL-4 and IL-5 production (68) and allergic lung inflammation in mice (69). Reasons for these discrepancies are presently unclear but could be due to fungal strain differences or to the impact of ASP on other cells beyond DCs, such as basophils or epithelial cells, which in those experimental systems could contribute to Th2 polarization (70)(71)(72).…”

Section: Discussionmentioning

confidence: 99%

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Zimmer

Luce

Gaignier

et al. 2011

The Journal of Immunology

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We characterized a new pathway to induce tolerogenic dendritic cells (DCs) following treatment of human monocyte-derived DCs with proteases from the fungus Aspergillus oryzae (ASP). ASP-treated DCs (ASP-DCs) exhibit a CD80−CD83−CD86−Ig-like transcript (ILT)2−ILT3−ILT4+ phenotype, do not secrete cytokines or chemokines, and express tolerogenic markers such as glucocorticoid-induced leucine zipper, NO synthetase-2, retinaldehyde dehydrogenase-1 or retinaldehyde dehydrogenase-2. When cocultured with naive CD4+ T cells, ASP-DCs induce an anergic state that can be reversed by IL-2. Generated T cells mediate a suppressive activity in third-party experiments that is not mediated by soluble factors. A comparison between dexamethasone-treated DCs used as a reference for regulatory T cell-inducing DCs and ASP-DCs reveals two distinct phenotypes. In contrast to dexamethasone, ASP treatment induces glucocorticoid-induced leucine zipper independently of glucocorticoid receptor engagement and leads to NF-κB p65 degradation. Abrogation of protease activities in ASP using specific inhibitors reveals that aspartic acid-containing proteases are key inducers of regulatory genes, whereas serine, cysteine, and metalloproteases contribute to NF-κB p65 degradation. Collectively, those features correspond to a previously unreported anergizing phenotype for human DCs. Such regulatory mechanisms may allow fungi to downregulate host immune responses and provide clues for new approaches to treat proinflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Zimmer

Luce

Gaignier

et al. 2011

The Journal of Immunology

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“…Allergic airway allergic inflammation was induced in mice as described (Kheradmand et al, 2002). Briefly, mice were anesthetized with isoflurane vapor (IsoFlo, Abbot-USA) and allowed to inhale 50 μL of a PBS suspension containing 5 μg of Aspergillus oryzae proteinase (Sigma) and 25 μg of ovalbumin (Sigma).…”

Section: Murine Airway Inflammationmentioning

confidence: 99%

A general method for bead-enhanced quantitation by flow cytometry

Montes

Jaensson

Orozco

et al. 2006

Journal of Immunological Methods

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Flow cytometry provides accurate relative cellular quantitation (percent abundance) of cells from diverse samples, but technical limitations of most flow cytometers preclude accurate absolute quantitation. Several quantitation standards are now commercially available which, when added to samples, permit absolute quantitation of CD4+ T cells. However, these reagents are limited by their cost, technical complexity, requirement for additional software and/or limited applicability. Moreover, few studies have validated the use of such reagents in complex biological samples, especially for quantitation of non-T cells. Here we show that addition to samples of known quantities of polystyrene fluorescence standardization beads permits accurate quantitation of CD4+ T cells from complex cell samples. This procedure, here termed single bead-enhanced cytofluorimetry (SBEC), was equally capable of enumerating eosinophils as well as subcellular fragments of apoptotic cells, moieties with very different optical and fluorescent characteristics. Relative to other proprietary products, SBEC is simple, inexpensive and requires no special software, suggesting that the method is suitable for the routine quantitation of most cells and other particles by flow cytometry.

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“…Many allergens relevant to human diseases, such as fungi, mite, cockroach, and pollens, have protease activities (29); these protease activities of allergens potently induce Th2-type immune responses in several experimental animal models (19,20). Our results provide a mechanistic understanding for these protease-related observations when AECs are exposed to environmental allergens.…”

Section: Discussionmentioning

confidence: 73%

“…Certain allergens are also proteases (e.g., Amb a from ragweed pollen; Bla g from cockroach; Asp f 5, f 6, and f 11 from Aspergillus; and Der p 1, p 3, p 9 from house dust mite [HDM]) (1). The protease activities produced by HDM, Aspergillus, or ragweed promoted a Th2 response (19,20). HDM proteases can activate protease-activated receptors (PARs), leading to allergic inflammation (21-23).…”

mentioning

confidence: 99%

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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A Protease-Activated Pathway Underlying Th Cell Type 2 Activation and Allergic Lung Disease

Cited by 290 publications

References 78 publications

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

A general method for bead-enhanced quantitation by flow cytometry

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

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