IL-23 and Th17 Cells Enhance Th2-Cell–mediated Eosinophilic Airway Inflammation in Mice

Wakashin, Hidefumi; Hirose, Koichi; Maezawa, Yoshiro; Kagami, Shin-ichiro; Suto, Akira; Watanabe, Norihiko; Saitō, Yasushi; Hatano, Masahiko; Tokuhisa, Takeshi; Iwakura, Yoichiro; Puccetti, Paolo; Iwamoto, Itsuo; Nakajima, Hiroshi

doi:10.1164/rccm.200801-086oc

Cited by 381 publications

(352 citation statements)

References 42 publications

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Section: Discussionsupporting

confidence: 94%

“…Blocking of IL-23 during the coculture of Per a 10 stimulated BMDCs and naive T cells reduced the secretion of Th2 type cytokines, implicating its role in protease induced Th2 responses. Our results are in accordance with a previous study where neutralization of IL-23 has led to reduction in Th2 cytokine production [32].Though immunotherapy with inactive Per a 10 was more effective than that of active Per a 10 in both cockroach extract sensitized [17] and Per a 10 sensitized mice the underlying mechanism remained to be elusive. Higher levels of IL-12p70 in the BALF of inactive Per a 10 immunized mice along with its higher secretion by inactive Per a 10 stimulated BMDCs might be a reason for the efficacy of inactive Per a 10 in immunotherapy.…”

supporting

confidence: 92%

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Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

2015

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Proteases are implicated in exacerbation of allergic diseases. In this study, the role of proteolytic activity of Per a 10 was evaluated on Th2 polarization. Intranasal administration of Per a 10 in mice led to allergic airway inflammation as seen by higher IgE levels, cellular infiltration, IL-17A, and Th2 cytokines, whereas, inactive ( )Per a 10 showed attenuated response. There was an increased OX40L expression on lung and lymph node dendritic cells in Per a 10 immunized group and on Per a 10 stimulated BMDCs. Reduction in CD40 expression without any change at transcript level in lungs of Per a 10 immunized mice suggested CD40 cleavage. BMDCs pulsed with Per a 10 showed reduced CD40 expression with lower IL-12p70 secretion as compared to heat inactivated Per a 10. IL-23, TNF-α, and IL-6 levels were significantly higher in Per a 10 stimulated BMDCs supernatant. In DC-T cell coculture studies, Per a 10 pulsed BMDCs showed higher levels of IL-4 and IL-13 that were reduced on blocking of either IL-23 or OX40L. In conclusion, the data suggests a critical role of protease activity of Per a 10 in promoting Th2 polarization by increasing IL-23 secretion and OX40L expression on dendritic cells.Keywords: CD40 r Cytokines r Dendritic cell r OX40L r Protease allergen Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionProteases are known to play an important role in manifestation of diseases like cancer, coagulopathies, respiratory inflammatory diseases, rheumatoid arthritis, and degenerative diseases [1][2][3]. Proteases from sources like house dust mite (Der p 1, Der p 3, Der p 6, Der p 9, Der f 1) and fungi (Asp f 13, Pen c 1, Pen c 13, Epi p 1) have been characterized as potent allergens [4]. Protease allergens act by proteolytic cleavage of an array of cell surface molecules and are known to modulate the functions of a variety of cell types including both immune and structural cells [5]. Proteolytic allergens from house dust mite are known to exacerbate allergic immune responses by selective cleavage of CD23, CD25, DC-SIGN, and DC-SIGNR on surface of immune cells Correspondence: Dr. Naveen Arora e-mail: naveen@igib.res.in; navdelhi@hotmail.com [6,7]. Further, cleavage and subsequent activation of PAR receptors by proteases lead to increased secretion of chemokines, proinflammatory, and pro Th2 cytokines from airway epithelial cells [8,9]. Studies have reported impaired epithelial barrier function as the feature of allergic diseases like asthma and atopic dermatitis [10]. The enzymatic activity of proteases has been reported to compromise epithelial barrier directly by cleaving tight junction proteins ZO-1 and occludin thereby increasing epithelial permeability [11,12]. Proteases can also act as adjuvants to bystander allergens present in the same microenvironment [13,14].Cockroaches have emerged as an important source of indoor allergens worldwide and cockroach extract is shown to be rich in proteases [15]. Previously, Per a 10, a serine protea...

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Section: Discussionsupporting

confidence: 94%

supporting

confidence: 92%

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

2015

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“…Hence passive transfer of CD47 high but not CD47 low polyclonal CD4 T cells induced eosinophilia and lung inflammation after 4 wk in nonlymphopenic mice. In support of our observations, adoptive transfer of in vitrogenerated Ag-specific Th17 cells initiates neutrophil recruitment in the airways with no inflammation, whereas cotransfer of Th17 and Th2 cell lines is required to promote a mixed neutrophilic and eosinophilic infiltration and airway hyperreactivity (AHR) (34). Collectively, our data favor the concept that Th17/Th2 doubleproducing cells, which are found in increased proportion in the circulation of patients with severe asthma (35) and identified as CD47 high in this study, are pathogenic and drive airway disease.…”

Section: Discussionsupporting

confidence: 72%

CD47high Expression on CD4 Effectors Identifies Functional Long-Lived Memory T Cell Progenitors

Van

Raymond

Baba

et al. 2012

The Journal of Immunology

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T cell memory is the hallmark of adaptive immunity. Central questions are to determine which cells among proliferating effector T cells will live beyond the crash of the immune response (IR) and develop into functional memory T cells. CD47, considered as a marker of self, is implicated in cell death, cell elimination, and in the inflammatory response. We report in this article that CD47 expression was transiently regulated on Ag-specific CD4 T cells, that is, from CD47high to CD47low to CD47high, during the course of the in vivo IR. Specifically, CD47high status marked central memory CD4 T cell precursors at an early time point of the IR. By contrast, cytokine production was a functional attribute restricted to CD47high, but not CD47low, polyclonal effector CD4 T cells during recall responses in an experimental model of chronic airway inflammatory disease. Passive transfer of CD47high, but not CD47low, CD4 T cells in nonlymphopenic naive mice generated long-lived memory T cells capable of anamnestic responses. We conclude that CD47high status on CD4 T cells identifies functional long-lived memory T cell progenitors.

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“…8). Furthermore, Wakashin et al (57) have reported that IL-23-mediated enhancement of Ag-induced neutrophil recruitment in the airway was reduced by the absence of IL-17, suggesting that IL-23 also contributes to neutrophilic airway inflammation through IL-17 production in this model.…”

Section: Discussionmentioning

confidence: 80%

Complement C3a-Induced IL-17 Plays a Critical Role in an IgE-Mediated Late-Phase Asthmatic Response and Airway Hyperresponsiveness via Neutrophilic Inflammation in Mice

Mizutani

Goshima

Nabe

et al. 2012

The Journal of Immunology

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Allergen-specific IgE plays an essential role in the pathogenesis of allergic asthma. Although there has been increasing evidence suggesting the involvement of IL-17 in the disease, the relationship between IL-17 and IgE-mediated asthmatic responses has not yet been defined. In this study, we attempted to elucidate the contribution of IL-17 to an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness (AHR). BALB/c mice passively sensitized with an OVA-specific IgE mAb were challenged with OVA intratracheally four times. The fourth challenge caused a late-phase increase in airway resistance associated with elevated levels of IL-17+CD4+ cells in the lungs. Multiple treatments with a C3a receptor antagonist or anti-C3a mAb during the challenges inhibited the increase in IL-17+CD4+ cells. Meanwhile, a single treatment with the antagonist or the mAb at the fourth challenge suppressed the late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid. Because IL-17 production in the lungs was significantly repressed by both treatments, the effect of an anti–IL-17 mAb was examined. The late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid was inhibited. Furthermore, an anti–Gr-1 mAb had a similar effect. Collectively, we found that IgE mediated the increase of IL-17+CD4+ cells in the lungs caused by repeated Ag challenges via C3a. The mechanisms leading to the IgE-mediated late-phase asthmatic response and AHR are closely associated with neutrophilic inflammation through the production of IL-17 induced by C3a.

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IL-23 and Th17 Cells Enhance Th2-Cell–mediated Eosinophilic Airway Inflammation in Mice

Abstract: IL-23 and Th17 cells not only induce Th17-cell-mediated neutrophilic airway inflammation but also up-regulate Th2-cell-mediated eosinophilic airway inflammation.

Cited by 381 publications

References 42 publications

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

CD47high Expression on CD4 Effectors Identifies Functional Long-Lived Memory T Cell Progenitors

Complement C3a-Induced IL-17 Plays a Critical Role in an IgE-Mediated Late-Phase Asthmatic Response and Airway Hyperresponsiveness via Neutrophilic Inflammation in Mice

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