Crucial Role of the Interleukin 1 Receptor Family Member T1/St2 in T Helper Cell Type 2–Mediated Lung Mucosal Immune Responses

Coyle, Anthony J.; Lloyd, Clare M.; Tian, Jane; Nguyen, Trang; Erikkson, Christina; Wang, Lin; Ottoson, Par; Persson, Per Olof; Delaney, Tracy; Lehar, Sophie M.; Lin, Steve; Poisson, Louis; Meisel, Christian; Kamradt, Thomas; Bjerke, T.; Levinson, Douglas A.; Gutierrez‐Ramos, José Carlos

doi:10.1084/jem.190.7.895

Cited by 346 publications

(295 citation statements)

References 25 publications

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“…This observation contrasts with those of Kurowska et al which showed that absence of IL-33 signalling does not affect IL-4 production [5,38]. This discrepancy can be explained by the difference in the asthma protocols or the doses of antigen administered during immunization [38][39][40]. Our model, using two sensitizations with low dose of OVA (10 mg/mouse) without adjuvant, followed by three OVA challenges (10 mg/mouse), seems to favour the development of classical Th2 cells that produce IL-4, IL-5 and IL-13, since we showed a reduction of all these cytokines in ST2-deficient mice.…”

Section: Discussionmentioning

confidence: 67%

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: 67%

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

et al. 2011

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“…Targeting ST2L via an antibody approach 18,21 or enhancing levels of sST2 24 have both proved effective in attenuating ovalbumin-induced allergic asthma responses in Th2-biased BALB/c mice. Our targeting of ST2L alone using a novel mAb in the fungal asthma model confirmed, and also extended, these previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…ST2-positive Th2 cells have been identified in experimental asthma models, 18,21 but the effect of allergic inflammation on the expression of ST2L by other lung cell types has not been previously examined. By using both IHC staining of whole lung tissue sections and ELISA analysis of whole lung homogenates, ST2L expression was determined immediately before (ie, day 0) and on days 7, 14, and 28 after i.t.…”

Section: Cell-associated St2l and Sst2 Expression In Experimental Andmentioning

confidence: 99%

“…Given that selective antibody-directed targeting of ST2 has been an effective therapeutic approach in other experimental asthma models, 18,21 we first examined whether targeting this receptor alone was efficacious in experimental fungal asthma. An mAb directed against mouse ST2 or an appropriate control IgG (both at a 100-g dose) was administered to asthmatic mice via i.p.…”

Section: Therapeutically Targeting St2l Alone Significantly Attenuatementioning

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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“…Increased serum levels of sST2 have been detected in a number of human diseases, including asthma and allergic airway inflammation, acute myocardial infarctions, and sepsis [10][11][12][13][14]. Although the biological significance for the increase in sST2 is not understood, several studies have demonstrated beneficial effects of sST2 treatment in animal models of diseases [2,4,6,15], suggesting that it may reduce inflammation. Intraperitoneal injection of IL-33 in mice resulted in splenomegaly, eosinophila and elevated serum IgE.…”

Section: Discussionmentioning

confidence: 99%

IL‐33 is a chemoattractant for human Th2 cells

et al. 2007

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IL‐33 is a novel cytokine of the IL‐1 family and mediates its biological effect via the receptor ST2, which is selectively expressed on Th2 cells but not Th1 cells. IL‐33 drives production of Th2‐associated cytokines including IL‐5 and IL‐13 and thereby promotes defense and pathology in mucosal organs. Cell locomotion is crucial to the induction of an effective immune response. We report here the chemoattraction of Th2 cells by IL‐33. Recombinant IL‐33 increased the proportion of human Th2 cells, but not Th1 cells, in polarized morphology in vitro and stimulated their subsequent invasion into collagen gels in an IL‐33 concentration‐dependent manner. Injection of recombinant IL‐33 into the footpad of ST2–/– mice which had been adoptively transferred with polarized Th2 cells, led to local accumulation of the transferred Th2 cells. These data therefore demonstrate that IL‐33 is a selective Th2 chemoattractant associated with the pro‐inflammatory property of this novel cytokine.

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Crucial Role of the Interleukin 1 Receptor Family Member T1/St2 in T Helper Cell Type 2–Mediated Lung Mucosal Immune Responses

Cited by 346 publications

References 25 publications

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

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

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

IL‐33 is a chemoattractant for human Th2 cells

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