Allergy. 2015 Apr;70(4):366-73.
IL-37 requires IL-18Rα and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice
Lars Lunding1, Sina Webering2, Christina Vock2, Alexandra Schröder1, Diana Raedler3, Bianca Schaub3, Heinz Fehrenbach2, Michael Wegmann1
1Division of Asthma Mouse Models, Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North, Member of the German Center for Lung Research, Borstel, Germany
2Division of Experimental Pneumology, Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North, Member of the German Center for Lung Research, Borstel, Germany
3 Department of Pulmonary & Allergy, University Children’s Hospital Munich, LMU Munich, Comprehensive Pneumology Center-Munich, Member of the German Center for Lung Research, Munich, Germany.
Michael Wegmann, PhD
Division of Mouse Models of Asthma, Priority Area Asthma & Allergy, Research Center Borstel (RCB), Parkallee 1-40, 23845 Borstel, Germany
Phone: +49 4537 188583
Background: Interleukin (IL) 37 has been described as negative regulator of innate immunity, since it reduces the activation and cytokine production of different innate immune cells. Recently, results from the CLARA childhood asthma cohort suggested an implication of IL-37 for human asthma pathogenesis. This study aimed to investigate the effects of IL-37 on allergic airway inflammation in a mouse model of experimental asthma.
Methods: Peripheral blood mononuclear cells (PBMCs) of children were cultured for 48h (anti-CD3/anti-CD28 stimulation or unstimulated), and IL-37 concentrations in supernatants were determined. Wildtype, IL-18Rα deficient (-/-) and SIGIRR-/- C57BL/6 mice were sensitized to ovalbumin (OVA), challenged with OVA aerosol to induce acute experimental asthma and IL-37 was applied intra-nasally prior each OVA challenge. Airway hyperresponsiveness (AHR), airway inflammation, cytokine levels in broncho-alveolar lavage fluid, and mucus production were determined.
Results: IL-37 production of human PBMCs was significantly lower in allergic asthmatics versus healthy children. In wildtype mice, intra-nasal administration of IL-37 ablated allergic airway inflammation as well as cytokine production and subsequently diminished hallmarks of experimental asthma including mucus hyperproduction and AHR. In contrast, local application of IL-37 produced none of these effects in mice lacking either IL18Rα or SIGIRR/IL-1R8.
Conclusions: This study demonstrates that IL-37 is able to ablate a TH2 cell directed allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18Rα as well as the orphan receptor SIGIRR/IL-1R8.
KEYWORDS: IL-18 receptor; IL-37; SIGIRR/IL-1R8; animal models, asthma
Allergic bronchial asthma is one of the most common chronic diseases worldwide actually affecting more than 300.000.000 patients (Masoli et al. 2004). Especially in industrialized countries high incidences reaching 7.5-19% of the population produce an enormous socioeconomic burden through medication costs, sickness absence, and hospitalization. Thus, elucidating the pathogenesis of this complex disease in order to identify novel targets for therapeutic intervention represents a prime target in recent allergy research.
The hallmarks of allergic asthma develop from a chronic inflammatory response in the airways. This chronic inflammation leads to recurrent destruction and subsequent remodeling of the airway tissues associated with enhanced mucus production and narrowing of the airways. In turn, this result in typical symptoms like cough, asthma attacks, respiratory distress and – in the worst case – to fatal broncho-obstruction. Thus, the key for understanding the pathogenesis of this disease lies in unraveling the regulation of the underlying chronic airway inflammation. During the initiation of allergic diseases such as allergic bronchial asthma the imbalance between T helper (TH) 1 and TH2 immune responses with predominant TH2 responses is critic ally important (Fig. 1 left). Subsequently, the pathological imbalance between excessive release of pro-inflammatory mediators and insufficient production of anti-inflammatory factors leads to chronification of the inflammatory response and, thus, to formation of the asthmatic disease (Fig. 1 A).
Figure 1: Different regulatory levels of allergic asthma. The imbalance of TH1 and TH2 immune responses during the initiation of the disease (left) and the inflammatory imbalance in favor of pro-inflammatory factors towards anti-inflammatory factors.
Interleukin 37 (IL-37) could be one of these anti-inflammatory factors involved in asthma pathogenesis. It is a barely investigated member of the IL-1 cytokine family and was initially described by Nold et al. to act as a fundamental inhibitor of innate immunity in 2010 (Nold et al. 2010). This study demonstrated for the first time an anti-inflammatory effect of IL-37 on dendritic cells in vitro and protective in vivo effects in an LPS shock mouse model. In the following years other studies dealing with the anti-inflammatory effects of IL-37 on different disease models of innate immunity like ischemia, sclerosis, colitis, and brain fever were published. However, the receptor and mechanism of action remained enigmatic.
Since we observed a diminished IL-37 production in allergic asthmatic patients compared to healthy controls, we hypothesized that IL-37 could also be involved in the pathogenesis of allergic asthma. In order to test this hypothesis, we used a classical allergic asthma mouse model and applied IL-37 locally to the lungs. Treatment with IL-37 significantly reduced hallmarks of experimental allergic asthma by points of allergic airway inflammation, pro-inflammatory cytokine production, and mucus production and improved lung function.
Subsequently, we asked how IL-37 unfolds its anti-inflammatory properties on experimental asthma and through which receptor these effect are mediated? Since it was described in cell free assays that IL-37 is able bind to the α-chain of the IL-18 receptor (IL-18Rα) (Pan et al. 2001), we hypothesized that IL-37 requires IL18Rα unit to provide its anti-inflammatory effects. Indeed, in animals deficient for IL18Rα treatment with IL-37 had no therapeutic effect on allergic airway inflammation and other hallmarks of experimental allergic asthma .
IL18Rα is a member of the IL-1 receptor (IL1R) family. The receptors of this family typically act as heterodimeric receptors consisting of a ligand-binding unit and an accessory unit leading to signal transduction. In search for a possible accessory receptor unit for IL-37 another member of the IL1R family seemed to be very promising. The receptor unit called single immunoglobulin and toll-interleukin 1 receptor (TIR) domain (SIGIRR) was described as orphan receptor with regulatory functions on IL-1R signaling (Riva et al. 2012). Thus, we hypothesized that IL-37 also requires the SIGIRR unit to provide its anti-inflammatory effects. We tested our hypothesis by using animals deficient for SIGIRR and also in these animals IL-37 treatment had no effect on allergic airway inflammation and hallmarks of experimental allergic asthma.
Therefore, we concluded from the data of the present study (Lunding et al. 2015) that IL-37 binds to a heterodimeric receptor consisting of IL18Rα and SIGIRR, which subsequently leads to anti-inflammatory signaling and blocking of pro-inflammatory signaling of the IL1R family (Fig. 2). These findings where later reconfirmed by other groups (Nold-Petry et al. 2015; Li et al. 2015).
Figure 2: Diagram of the concluded IL-37 receptor consisting of IL18Rα and SIGIRR that could inhibit pro-inflammatory IL1-family of cytokines signaling (e.g. IL-18)
Importance of the study: The data of this study demonstrated for the first time that IL-37 is able to ameliorate the allergic immune response and hallmarks of experimental asthma which requires IL18Rα as well as the orphan receptor SIGIRR. Since IL-37 levels are decreased in patients with allergic asthma, IL-37 and its receptor thus represent novel targets for therapeutic intervention in allergic bronchial asthma.
Acknowledgements: This study was supported by grants from the German Federal Ministry of Education and Research (BMBF) to the German Center for Lung Research (DZL).
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