Anti-IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma

Liu, Xiaojin; Li, Mingcai; Yan, Wei; Zhou, Yanchun; Zeng, Liangming; Huang, Tianhua

doi:10.1016/j.bbrc.2009.06.008

Cited by 196 publications

(154 citation statements)

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“…Recently, it was shown that the resolution of allergic inflammation and airway hyperresponsiveness depend on the disruption of ST2/IL-33 pathway [8] and that IL-33-neutralizing antibody administration inhibits airway inflammation in mice [37]. Using ST2-deficient mice, we demonstrated here that IL-33 signalling is necessary upon antigen sensitization to mount an efficient Th2 response.…”

Section: Discussionmentioning

confidence: 66%

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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Section: Discussionmentioning

confidence: 66%

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

et al. 2011

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“…33,40 Although controversy exists about whether caspase-mediated cleavage of IL-33 produces an active or inactive form of the protein, 16,41,42 IL-33-mediated activation of various lymphoid, myeloid, and epithelial cells via ST2L leads to profound changes in the lung, including airway hyperresponsiveness and goblet cell metaplasia. 20 Various targeting strategies directed at either IL-33 25 or ST2L 18 -22 have proved successful in the treatment of experimental allergic asthma, largely through the reduction in Th2-type inflammation. In the present study, we observed that both ST2L and IL-33 were induced after the challenge of A. fumigatus-sensitized mice with live conidia from the same fungus.…”

Section: Discussionmentioning

confidence: 99%

“…17 With this background, we hypothesized that the enhanced expression of ST2L during Th2-driven allergic inflammatory responses impeded the TLR9-dependent therapeutic effects of CpG in a model of fungal asthma, which was previously determined to be responsive to local (ie, lung), but not systemic, CpG therapy. 8 Although the therapeutic effects of targeting ST2L, 18 -22 increasing soluble ST2 (sST2) levels, 23,24 or targeting IL-33 25 activity in experimental asthma have been previously examined, it is not known whether the therapeutic effect of targeting IL-33/ST2L is related to enhanced TLR9 activation in this setting. In the present study, the combination of systemic CpG and an anti-ST2L monoclonal antibody (mAb) markedly reduced the severity of all features in this chronic fungal asthma model, whereas the administration of either treatment alone had no therapeutic effect at the selected doses.…”

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confidence: 99%

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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“…6A). Because M2 macrophages play an important role in asthma by producing chemokines and mediating tissue fibrosis (20,27,35), we investigated the phenotype of the recipients' macrophages. BAL cells were stained for F4/80, CCR3, MR (an M2 macrophage marker), and TLR2 (a marker of proinflammatory subset of macrophages, M1).…”

Section: Il-33-activated Eosinophils Induce Airway Inflammation In Stmentioning

confidence: 99%

“…The pathogenic role of IL-33 in airway inflammation emerged from experiments with intranasal administration of IL-33 into naive mice that then exhibited eosinophilia and high concentrations of IL-5, IL-13, chemokines, IgE, and mucus production in the lungs, as well as airway hyperresponsiveness (16,24,26). Moreover, IL-33 was able to exacerbate airway inflammation induced by Ags (22,27,28). Examination of the cell types involved in these processes revealed the contribution of IL-33-activated alternatively activated (M2) macrophages (24).…”

mentioning

confidence: 99%