IL-33–activated dendritic cells induce an atypical TH2-type response

Rank, Matthew A.; Kobayashi, Takao; Kozaki, Hideaki; Bartemes, Kathleen R.; Squillace, Diane L.; Kita, Hirohito

doi:10.1016/j.jaci.2009.02.026

Cited by 345 publications

(280 citation statements)

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“…36 IL-33-activated DCs induce what has been described as an atypical Th2-type response characterized by IL-5 and IL-13, with no IL-4. 37 The addition of recombinant IL-33 to cultured asthmatic DCs in the present study dose dependently induced chemokine ligands 17 and 22, but not IL-12p70, generation by these cells (H.R. and C.M.H., unpublished data).…”

Section: Discussionmentioning

confidence: 51%

“…allergic asthma, 43 including attenuation of asthmatic responses driven by both fungus 37 and fungal proteases. 54 The role of MIG/CXCL9 in asthma is less clear, but this CXC chemokine is strongly induced by IL-12.…”

Section: Discussionmentioning

confidence: 99%

“…37 Because DCs exert a prominent effect on the development and maintenance of allergic inflammation, we examined the expression of ST2L and IL-33 in naïve and asthmatic DCs at various times after the conidia challenge. ST2L transcript levels in bone marrow-derived DCs from asthmatic mice were induced above levels in naïve DCs, most notably on days 14 and 28 after the conidia challenge ( Figure 3A).…”

Section: Dcs From Asthmatic Mice Express Greater St2l Transcript and mentioning

confidence: 99%

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Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Ramaprakash

Shibata

Duffy³

et al. 2011

The American Journal of Pathology

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IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Dcs From Asthmatic Mice Express Greater St2l Transcript and mentioning

confidence: 99%

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Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Ramaprakash

Shibata

Duffy³

et al. 2011

The American Journal of Pathology

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“…Myeloid DCs generated in the presence of IL-33 exhibit a relatively limited T-cell stimulatory capacity compared with conventional DC cultures established with GM-CSF. On the other hand, Rank et al reported that mature DC treatment with IL-33 upregulated cell-surface expression of MHC class II molecules and the costimulatory molecule CD86 [29]. Furthermore, IL-33-activated DCs could polarize CD4 1 T cells to produce IL-5 and IL-13, suggesting that IL-33 may play a role in the induction of adaptive immune responses.…”

Section: Introductionmentioning

confidence: 99%

“…The cytokine expression pattern of T cells polarized by IL-33-activated DCs differs from classical Th2 cells by the absence of IL-4 production. An atypical Th2 subset upon IL-33 activation has been reported, which is independent of IL-4, GATA3 and TCR engagement [26,29].The contribution of IL-33 on asthma symptoms by its direct action on mast cells, basophils, eosinophils and Th2 cells has been Figure 7. IL-33 enhances allergic airway inflammation induced by OVA-pulsed DCs.…”

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confidence: 99%

IL‐33‐activated dendritic cells are critical for allergic airway inflammation

et al. 2011

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IL-33, a new member of the IL-1 family cytokine, is involved in Th2-type responses in a wide range of diseases and signals through the ST2 receptor expressed on many immune cells. Since the effects of IL-33 on DCs remain controversial, we investigated the ability of IL-33 to modulate DC functions in vitro and in vivo. Here, we report that IL-33 activates myeloid DCs to produce IL-6, IL-1b, TNF, CCL17 and to express high levels of CD40, CD80 OX40L and CCR7. Importantly, IL-33-activated DCs prime naive lymphocytes to produce the Th2 cytokines IL-5 and IL-13, but not IL-4. In vivo, IL-33 exposure induces DC recruitment and activation in the lung. Using an OVA-induced allergic lung inflammation model, we demonstrate that the reduced airway inflammation in ST2-deficient mice correlates with the failure in DC activation and migration to the draining LN. Finally, we show that adoptive transfer of IL-33-activated DCs exacerbates lung inflammation in a DC-driven model of allergic airway inflammation. These data demonstrate for the first time that IL-33 activates DCs during antigen presentation and thereby drives a Th2-type response in allergic lung inflammation. IntroductionAllergic asthma is a chronic disorder characterized by eosinophilic airway inflammation, mucus hypersecretion, antigenspecific-IgE antibodies, airway remodeling and increased airway hyperreactivity [1,2]. The process of airway inflammation involves various cells types, such as eosinophils, mast cells, epithelial cells, lymphocytes and DCs. Th2 cells have been shown to play a predominant role in allergic asthma and Th2 cytokines, such as IL-4, IL-5 and IL-13, exacerbate disease severity [3,4]. IL-33, the recently discovered Th2 cytokine, is found at high levels in the plasma of asthmatic patients [5,6] and in the lungs of mice during experimental allergic asthma [7,8].IL-33 is a member of IL-1 family [9][10][11]. Like IL-1b or IL-18, IL-33 is synthesized as a precursor and can be cleaved by caspase-1 and 3 but the cleavage products are biologically less active than the precursor [12,13]. In contrast to the other IL-1 family members, IL-33 is mainly expressed in non-hematopoietic cells such as fibroblasts, epithelial cells and endothelial cells [10,14,15]. Because of its nuclear localization sequence, IL-33 is usually present in the nucleus, where it acts as a potential transcriptional repressor [16]. Recently, IL-33 has been shown to be released from necrotic cells and may act as an alarmin in a similar manner to IL-1a [17] or high mobility group box1 protein HMGB1 [18,19]. [14]. In accordance with its Th2 functions, administration of IL-33 into naive mice induces severe inflammation in the lung and digestive tract with elevated levels of IL-4, IL-5 and IL-13, splenomegaly and increased serum Ig [10]. In vitro, IL-33 has also been reported to polarize naive CD4 1 T cells to produce IL-5 and IL-13, but not . Polarization of this atypical Th2 population is independent of IL-4, STAT6 and GATA3. On macrophages, IL-33 amplifies IL-13-mediated polarization...

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Novel Anti‐Inflammatory Drugs Based on Targeting Lung Dendritic Cells and Airway Epithelial Cells

Lambrecht

Plantinga

Willart

et al. 2011

Inflammation and Allergy Drug Design

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IL-33–activated dendritic cells induce an atypical TH2-type response

Abstract: Background-IL-33, a recently discovered IL-1 family cytokine, is implicated in the development of Th2-type responses in vivo. However, the cellular target(s) for IL-33 are poorly understood.

Cited by 345 publications

References 49 publications

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

IL‐33‐activated dendritic cells are critical for allergic airway inflammation

Novel Anti‐Inflammatory Drugs Based on Targeting Lung Dendritic Cells and Airway Epithelial Cells

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