The potential of interleukin-37 as an effective therapeutic agent in asthma

Interleukin (IL)-37 was first described using in silico research in 2000, and increasing evidence has recently demonstrated that IL-37 has profound immunoregulatory functions [1‐4]. These include cell proliferation, differentiation, suppression of acquired immunity, and limiting of innate inflammation (Fig. 1). IL-37 is a member of the IL-1 cytokine family that binds to IL-18Rα, which prevents it from binding IL-18 [5]. To date, 11 members have been identified that belong to the IL-1 family. Seven of those components (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ) have pro-inflammatory activities, while there are four antagonists, including IL-1R antagonist, IL-36R antagonist, IL-37, and IL-38 [6]. The only member of the IL-1 family where simian and murine homologues remain undiscovered is IL-37 [3, 7]. In humans, the IL-37 gene is located on chromosome 2 next to genes encoding 8 other members of the IL-1 family. Five splice transcript variants encode distinct isoforms of IL-37 (IL-37a-e) [1‐4, 8]. IL-37b is the largest among the isotypes, and has 5 of the 6 exons [9, 10].

In the last decade, research has extensively demonstrated functions of IL-37 in both the innate and adaptive immune system. IL-37 suppresses the production of pro-inflammatory cytokines such as TNF-α, IL-1α, IL-1β, IL-6, G-CSF and GM-CSF from human blood LPS-stimulated monocytes [3, 11]. IL-37 can also reduce neutrophil infiltration into the lung [12] and monocyte infiltration following myocardial infarction [13]. Furthermore, it decreases dendritic cell (DC) activation and has a suppressive action in adaptive immunity [14]. Therefore, the main function of IL-37 is believed to be the reduction of excessive inflammation in both the adaptive and innate immune system through means of negative feedback [15].

IL-37 can exert its anti-inflammatory effects in both intracellular and extracellular conditions. After synthesis, one third of the IL-37b precursor is cleaved intracellularly and then translocated to the nucleus. This process is likely to be associated with Smad3 [3, 16]. On the other hand, cells transfected with IL-37 release an IL-37 precursor after LPS stimulation, which is independent of caspase-1 cleavage at D20 [17]. Extracellular IL-37 executes its anti-inflammatory effects by preventing IL-18Rα from adhering to IL-18 and recruiting the orphan decoy IL-1R8 to the IL-18Rα/IL-37/ IL-1R8 complex (Fig. 1) [11, 18, 19]. Neutralizing antibodies against IL-37 can enhance production of pro-inflammatory cytokines when it is either administered in vitro or in vivo [17, 20].

In recent decades, research activity focusing on IL-37 has increased rapidly. This might be due to the long list of diverse functions demonstrated by IL-37, and its active role in the physiopathology of multiple diseases (Table 1) including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and asthma. This present review summarizes the published literature on the functions and mechanisms of IL-37 in both humans and experimental models, and explores its role in the pathophysiology of asthma.

IL-37 is expressed by a wide range of different tissue and cell types under normal physiological conditions. Cells and tissues that express IL-37 include human blood monocytes, plasma cells, synovial cells, tissue macrophages, tonsillar B cells, epithelial cells (skin and intestine), neoplastic cells, and kidney cells [3]. The level of IL-37 was markedly augmented at 24 h and 72 h in human IL-37-expressing transgenic mice (hIL-37tg mice) after spinal cord injury, while it was barely detectable under normal conditions [21]. The extracellular concentration of IL-37 is aberrantly expressed in a number of inflammatory diseases in humans. Increased levels of IL-37 have been detected in plasma and PBMCs from HIV-1-infected subjects compared to non-infected individuals [22]. Similar results were reported when the serum and synovial fluid of patients with RA was examined, and serum from patients with Graves’ disease also has increased levels of IL-37 [23‐25]. In RA patients, IL-37 levels significantly correlated with the rheumatoid factor (RF) value, disease activity, and the levels of IL-4, IL-7, IL-10, IL-12, and IL-13. The plasma level of IL-37 is also decreased in those who respond to treatment with disease-modifying anti-rheumatic drugs (DMARD) [23, 25, 26]. However, the opposing phenomenon is observed in some other diseases. For example, in Behcet’s disease (BD), both mRNA and protein expression of IL-37 was significantly reduced in PBMCs from patients with active disease compared to non-diseased individuals [27]. Moreover, decreased production and expression of IL-37 was also noted in re-stimulated PBMCs from children with allergic bronchial asthma [19, 28].

Both surface expression and intracellular production of IL-37 increase following stimulation with pro-inflammatory cytokines IL-1β, IL-18, TNF-α, and IFN-γ, and anti-inflammatory cytokines TGF-β, IL-10, as well as various toll-like receptor (TLR) ligands [3, 29]. The level of IL-37 in human blood monocytes and DCs rapidly increases under inflammatory conditions, even though it is very low under basal conditions [3, 14, 30]. The inflamed mucosa of IBD patients expressed very high IL-37b levels compared to the normal colonic mucosa evaluated by immunohistochemistry, real time-polymerase chain reaction (PCR), and Western blotting [31]. Similar results were also obtained from the epithelial cells and submucosal lymphoid cells of pediatric patients with chronic IBD [32]. Flow cytometry of circulating B cells, active natural killer cells, and monocytes in patients with IBD showed increased production of IL-37 compared to the control group [33]. Interestingly, endogenous glial cells are likely to be the early source of IL-37 in mice spinal cords, while macrophages are the main IL-37-expressing cells in IL-37tg mice after several types of inflammatory challenge [3, 30, 34]. This is supported by the low level of leukocyte infiltration at the early stages of the immune response instead of endogenous glial cells [35].

Inflammatory states in general are likely to increase the expression of IL-37. For example, IL-37 expression was found to have a non-independent positive association with viral infection [36]. Furthermore, chronically infected HBV patients with high viral loads had higher serum levels of IL-37 compared to non-infected individuals [37]. Environmental stimuli can also affect the production of IL-37. Di Stefano and colleagues reported that smokers had decreased expression of IL-37 in the submucosa compared with healthy non-smokers [38].

In the murine ovalbumin (OVA) model of allergic asthma, IL-37 has been shown to have remarkable anti-inflammatory properties. Eosinophil numbers in BAL and airway tissue are significantly reduced by local administration of IL-37. However, administration of IL-37 did not change the numbers of macrophages, lymphocytes, or neutrophils. Examination of periodic acid Schiff (PAS)-stained airway cross-sections showed that IL-37 markedly reduced goblet cell hyperplasia in the OVA-model. Moreover, methacholine provocation indicated that IL-37 could also reduce airway hyper-reactivity (AHR) in asthmatic mice. Treatment of experimental asthma with intranasal rhIL-37 resulted in significantly decreased production of Th2-type cytokines, such as IL-4, IL-5, and IL-13 as well as pro-inflammatory cytokines such as IL-6. Furthermore, the anti-inflammatory action of IL-37 depended on IL18Ra as well as the orphan receptor SIGIRR/IL-1R8 [19].

Asthma is characterized by chronic airway inflammation caused by abnormal T-cell responses [48]. The inflammation is finely modulated by CD4+ T lymphocytes, including Th1, Th2, and Th17 cells [49]. The infiltration of inflammatory cells and release of inflammatory factors leads to increased bronchial contractions termed AHR and asthmatic symptoms such as wheezing, shortness of breath, and chest tightness [50].

Asthma is a heterogeneous disease, and increased efforts have been made in sub-typing the different phenotypes of asthma. A common method of sub-typing asthma assesses the presence of different inflammatory cells found in induced sputum. Asthma can thereby be classified into four different groups: eosinophilic asthma, neutrophilic asthma, paucigranulocytic asthma, and mixed granulocytic asthma. Each sub-type responds to therapy differentially due to distinctly different immunological mechanisms [51‐53]. Crucial to the development of “personalized medicine” is the recognition that asthma is not one homogenous disease but that different sub-types of asthma exist. Classical eosinophilic asthma is the best-characterized sub-type and involves allergen-induced activation of Th2 pathways and release of Th2 cytokines such as IL-4, IL-5, IL-9, and IL-13 [54]. Eosinophilic asthma responds well to corticosteroids, which are the first-line therapy currently used against asthma. Neutrophilic asthma, on the other hand, is driven by the activation of the innate immune system including TLRs and NLRP3 inflammasomes by infections and environmental pollutants [55, 56]. This sub-type of asthma is less well-characterized and notoriously resistant to corticosteroid treatment.

IL-37 plays different roles in the pathogenesis of the different phenotypes of asthma. IL-17, which can be suppressed by IL-37 [45], is involved in both neutrophilic and eosinophilic asthma. IL-17 produced by Th17 cells or macrophages not only promotes the infiltration of neutrophils into the lung but recent evidence also suggests that it can contribute to the development of allergic eosinophilic asthma [57, 58], where it acts synergistically with Th2 cytokines to promote AHR [57, 59, 60].

IL-37 can suppress Th1, Th2, and Th17 effector responses to modulate inflammatory responses (Fig. 2) [19, 45]. Defective IL-37 signaling can lead to both Th2- and Th1-mediated inflammatory diseases [23, 25, 26], including asthma [19].

Despite the sound theoretical possibility, the role of IL-37 in asthma is still not well established. Charrad and colleagues found that IL-37 mRNA expression in serum and induced sputum was significantly lower in asthmatic patients than healthy controls, and that IL-37 mRNA expression was associated with asthma severity [42]. Similar data were reported by Lunding et al., who found significantly lower IL-37 production in human PBMCs from children with allergic asthma compared to healthy controls. Furthermore, treatment of PBMCs with anti-CD3/anti-CD28 decreased IL-37 expression in supernatants from asthmatic samples [19]. These results were confirmed by Raedler and colleagues who also found decreased IL-37 expressions in those with allergic asthma compared to healthy controls [28]. A non-allergic asthma group was also included in this study and patients with non-allergic asthma exhibited increased expression of IL-37 compared to those with allergic asthma [28]. Interestingly, recombinant IL-37 has been shown to partially suppress TSLP production in bronchial epithelial cells from asthmatic patients [46]. These contradictory observations from experimental data might be due to the heterogeneity of asthma and explained by the differences in the sub-types of asthma that were studied. Thus, additional studies with carefully phenotyped asthmatic patients are required to fully characterize the expression of IL-37 in asthmatic patients.

Despite robust evidence showing that IL-37 is an important regulator of inflammatory cell infiltration, activation, and clearance in experimental models, data on the levels and functions of IL-37 in human asthma is still limited. Recent studies using the OVA model of asthma indicate that IL-37 exerts anti-inflammatory effects in vivo and also suppresses allergen-induced AHR. The lack of consistent data in humans might be due to the heterogeneity of asthma. Thus, additional studies with carefully phenotyped asthmatic patients are required to be able to fully characterize the expression of IL-37 in this disease. Targeting the actions of IL-37 might represent a promising strategy for the development of effective therapeutic agents against asthma.