Targeting cytokines in asthma therapy: could IL-37 be a solution?

KEYWORDS:

• Asthma
• cytokine
• inflammation
• interleukin 37
• neutralization

Patients suffering from bronchial asthma display a number of symptoms including productive coughing, wheezing, chest tightness, and shortness of breath due to increased mucus production, airway hyperresponsiveness (AHR) and episodes of broncho-obstruction. Depending on the severity of the disease, most symptoms appear recurrently but with a considerable variation of intensity and frequency leading the recognition of asthma as a complex and heterogeneous disease syndrome and to the formulation of different asthma phenotypes/endotypes [1]. However, since in most cases this complex disease syndrome arises on the basis of a chronic inflammatory response in the airways, the key strategy of asthma therapy is to reduce airway inflammation [2]. Consequently, oral and/or inhalative corticosteroids (CS) represent the standard treatment option for asthma patients since the 1960s [3]. Unfortunately, CS produce considerable side effects with increasing doses and especially when delivered systemically, and patients with low eosinophil counts are less responsive to CS treatment [4]. Thus, over the last two decades, asthma research concentrated on elucidating the mechanisms underlying the initiation, progression, and chronification of airway inflammation in order to unravel novel targets for therapeutic intervention.

Beginning in the 1990s, the use of appropriate mouse models of experimental asthma helped to characterize T helper 2 (TH2) cells as key players in the pathogenesis of allergic asthma. By releasing a typical array of cytokines and growth factors like interleukin-4 (IL-4), IL-5, IL-9, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF), these TH2 cells orchestrate the allergic immune response in the airways that underlies the formation of the disease. Neutralization of each of these cytokines markedly improved disease symptoms in mouse models of experimental allergic asthma [5]. Consequently, the development of monoclonal antibodies and other biologicals targeting their human equivalents lead to the identification of several promising candidates for novel asthma treatment options.

Although showing promising preclinical results, targeting IL-4 (pascolizumab [6], pitrakinra [7], AMG-317 [8]) failed to improve asthma symptoms in clinical trials and appears to be ineffective in established disease. Also antibodies neutralizing IL-9 (MEDI-528 [9]) or IL-13 (lebrikizumab [10], GSK679586 [11], IMA-026 [12]) were discontinued due to lack of efficacy in clinical asthma trials. While another IL-13 neutralizing antibody (tralokinumab [13]) is now tested phase III clinical trial, to date only anti-IL-5 antibodies (benralizumab [14], mepolizumab [15], reslizumab [16]) have been approved for treatment of severe persistent, allergic asthma with high eosinophil counts. The relatively modest effects of these candidates for asthma therapy emphasized that asthma is a complex disease syndrome with many phenotypes/endotypes, which require tailored therapy, and that targeting TH2-cytokines could be a treatment option in a special population of asthma patients displaying hypereosinophilia.

Consequently, proinflammatory cytokines that are not specifically involved in allergic immune responses but rather generally contribute to initiation and continuation of inflammatory reactions such as IL-1β, IL-17, and tumor necrosis factor (TNF) α moved into focus. Surprisingly, a number of attempts to neutralize the activity of these factors with antibodies like canakinumab, brodalumab [17], adalimumab, golimumab [18], and infliximab did not produce convincing results in clinical trials [19]. None of these agents reduced inflammatory cell counts or produced significant improvements of the clinical outcomes, but raised serious concerns over the safety of TNF-α-blockade and an increased susceptibility to respiratory infections.

Although further antibodies (e.g. ixekizumab, secukinumab, tezepelumab) neutralizing the proinflammatory activity of cytokines like IL-17, IL-33, and thymic-stromal lymphopoietin (TSLP) [20–22] are currently under investigation and produced promising results in animal disease models, one could assume that just inhibiting the proinflammatory factors may not the ideal solution for asthma therapy. Indeed, it could also be an option to support the anti-inflammatory response in order to counterbalance airway inflammation. Unfortunately, in contrast to the plethora of cytokines that has been discovered over the last years to conduct allergic inflammatory processes, the number of regulatory cytokines is surprisingly small. Among those factors are rather specific molecules like the soluble TNF-α receptors (sTNF-αR) or IL-1RA that neutralize the functions of their respective cytokines or generally anti-inflammatory cytokines such as TGF-β and IL-10 that inhibit the proinflammatory activities of IL-1β, IL-6, TNF-α, GM-CSF, and interferon γ [23,24]. While the sTNF-αR termed etanercept revealed no efficacy in patients with mild-to-moderate asthma [25], treatment with recombinant human IL-10 (rhIL-10) or TGF-β is rather critical due to expected side effects: TGF-β is a potent anti-inflammatory cytokine but also displays very potent pro-fibrotic properties and treatment with higher doses of rhIL-10 lead to flu-like episodes, transient neutrophilia, and decreased numbers of lymphocytes and thrombocytes in clinical trials [26]. Furthermore, IL-10 upregulation has been shown to play a critical role as inducer of TH2 responses in asthma. Listing all these setbacks – and keeping in mind the quite recent realization that asthma is a complex and heterogeneous disease syndrome comprising different phenotypes and endotypes – one could doubt that addressing single cytokines is really a realistic chance to successfully treat asthmatic patients. Thus, it could be more promising to target more than one of the above-mentioned cytokines or even an entire cytokine network at the same time. One step in this direction could be an antibody directed against the alpha chain of the IL-4 receptor that is not only used by IL-4 but also by IL-13 (dupilumab). Consequently, this approach interferes with the effects of both TH2-type cytokines and recently displayed encouraging results in clinical trials [27]. Combinatorial targeting of the three cytokines TSLP, IL-25, and IL-33 displayed synergistic anti-inflammatory effects in a mouse model of TH2-type inflammation, highlighting the potential of such combined targeting strategies [28].

Maybe cytokine therapy as an approach for asthma treatment went even a step further with the first description of the IL-1 family member 7 as a cytokine termed IL-37 in 2010 [29]. The first studies described a dampening effect of this new cytokine on the activity of several innate immune cells in reaction to lipopolysaccharide (LPS) stimulation. Consequently, it has been presented as a fundamental inhibitor of innate immune responses. The last three years saw an encouraging research activity in this field and a bunch of studies that characterized the regulatory activity of IL-37 and its mode of action. These studies demonstrated that IL-37 is capable of inhibiting proinflammatory effects that are mediated through activation of receptors belonging to the interleukin-1 receptor/toll-like receptor (TIR) superfamily like TIRs 2 and 4 and the IL-1 receptor [30,31]. As shown in in vitro and in a wide range of animal models for chronic inflammatory diseases, this inhibition on the one hand results in further diminished production of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-17, IL-23, GM-CSF, and TNF-α and chemokines like CCL12, CXCL1, CXCL2, CXCL8, and CXCL13 [32–34]. On the other hand, IL-37 has been described to support IL-10 production, tolerogenic dendritic cell, and regulatory T cell activity [34,35]. So far, its mode of action includes interference with the inflammasome, an intracellular activity as well as extracellular binding to IL-18 receptor α and the regulatory orphan receptor SIGIRR/IL-1R8 [31,32,36,37]. All these observations suggested that IL-37 could be a potent regulator of local innate immunity. However, quite recently, it was discovered that the expression and production of IL-37 is reduced in patients suffering from allergic disease rising the hypothesis that such a decreased production of an anti-inflammatory cytokine could be associated with an impaired capacity to counterbalance ongoing inflammatory processes and, thus, could predispose toward the development of a chronic inflammatory disease such as asthma [37,38]. This hypothesis is supported by the finding that local treatment of animals with experimental allergic asthma dramatically reduced all hallmarks of the disease by points of allergic airway inflammation, mucus hypersecretion, and AHR and surprisingly dampened TH2 cell activity and TH2-type cytokine release [37]. Additionally, IL-37 has been described to not only suppress the activity of mast cells but also reverses the metabolic cost of inflammation in smooth muscle cells [39,40]. These studies clearly demonstrate that IL-37 has not only the capacity to regulate innate immune cells but also allergic inflammatory responses and to limit the direct consequences of these processes.

Although no clinical trials on IL-37 have been performed so far, in summary, these new findings point out the widespread regulatory functions of IL-37 that interfere with various inflammatory mechanisms being described for most of the recently defined asthma pheno/endotypes. Thus, in contrast to neutralization of single proinflammatory cytokines, the supplementation with IL-37 offers the potential to use multiple regulatory functions as a novel treatment option for the majority of asthma patients.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Additional information

Funding

This manuscript has been supported by the German Center for Lung Research (DZL) (DZL DA-AA-TFP and DZL LI-JRG-1) and the Federal Ministry of Education and Research (BMBF) (BMBF 13N13857).