Next-Generation Therapeutic Approaches for Uncontrolled Asthma: Insights Into the Heterogeneity of Non-Type 2 Inflammation

Asthma is a chronic airway inflammatory disorder with heterogeneous pathogenic causes and various phenotypes. The phenotype of uncontrolled asthma (UA) poses a significant burden to patients and society and is, in many cases, preventable.1 The potential negative consequences of UA include risk of exacerbations,2 adverse effects of oral corticosteroid (OCS) use,3, 4, 5 and reduced quality of life (QoL).6 There are numerous complex reasons why asthma may remain uncontrolled despite treatment, including inappropriate management and assessment,7, 8, 9, 10 poor adherence to treatment,9, 11, 12, 13 incorrect inhaler technique,14, 15 and treatment resistance. Therefore, efforts have been made to overcome UA through enhancing shared decision-making and communication between patients and physicians, patient education and self-management, risk assessment, close monitoring to reduce asthma exacerbations, and appropriate therapeutic interventions.1 As clinicians, one of the most promising solutions for UA is developing and applying new therapeutics based on the pathophysiology of treatment-resistant UA. Over the past decade, therapeutic outcomes for severe asthma (i.e., treatment-resistant UA) have improved with various cytokine-targeted biological agents and decreased OCS use. With the use of these biologics, the treatment goal for asthma has shifted from ‘control’ to ‘remission.’16 However, these treatments are expensive and only applicable to patients with severe asthma who do not respond to current standard treatments. In fact, the most well-defined endotype of asthma is type 2 (T2)-high asthma, which is associated with eosinophilia in the blood and/or sputum. Currently, add-on biological treatments are available for T2-high asthma such as severe eosinophilic or allergic asthma since they target immunoglobulin E, interleukin (IL)-5, IL-5Rα, and IL-4Rα.17 Considering the breakthroughs in the treatment of severe asthma, in particular the T2-high endotype, using these biologics, the development of non-T2 targeted therapeutic options to overcome treatment-resistant UA is eagerly awaited.

In this issue of Allergy Asthma and Immunology Research, Quoc et al.18 showed that IL-33 induces neutrophilic activation via suppression of the tumorigenicity 2 (ST2) pathway in UA. Neutrophil extracellular traps isolated from patients with UA stimulated the differentiation of M1 macrophages and type 3 innate lymphoid cells (ILC3), contributing to non-T2 airway inflammation. More interestingly, these authors demonstrated the potential of soluble ST2 (sST2) as a diagnostic biomarker for UA beyond its typical role as a decoy receptor for IL-33. When asthmatic patients were classified into sST2-high and sST2-low groups using an sST2 cutoff value of 15.0 ng/mL, the sST2-high group had a significantly higher prevalence of UA and severe asthma. In addition, higher levels of serum myeloperoxidase (MPO), IL-8, and S100A9 in the sST2-high group suggested that sST2 could be associated with asthma control status and severity as well as neutrophilic airway inflammation. Patients with UA are frequently exposed to OCS, which may further augment neutrophilic airway inflammation. It is well known that the association between neutrophil counts in sputum and peripheral blood is very weak, and peripheral blood neutrophilia is one of the predictors of asthma exacerbation and a poorly controlled asthmatic state.19, 20 Thus, asthmatic neutrophilic inflammation appears heterogeneous and can be grouped into various subtypes such as systemic or airway-localized type. Although Quoc et al.18 could not evaluate the inflammatory endotypes of patients with UA due to the small number of patients in the UA group in their study, the representative neutrophilic inflammatory mediators, MPO, IL-8, and S100A9, were correlated with the serum level of sST2. Given that there are currently no available serum biomarkers for neutrophilic asthmatic inflammation, these findings regarding the biomarker potential of sST2 in asthmatic patients are noteworthy.

Non-eosinophilic asthma has been accepted as non-T2 asthma, which is less well characterized. Defining non-T2 inflammation by the absence of an elevated eosinophil count remains problematic since non-T2 biology may encompass heterogeneous endotypes. Non-T2 asthma can be further classified into neutrophilic and paucigranulocytic types depending on the cellular findings in sputum specimens.21 In practice, non-T2 asthma is diagnosed based on a low blood eosinophil count and low exhaled nitric oxide fraction. Non-T2 asthma has not responded to existing biologic agents, although very recently, tezepelumab was approved for the treatment of severe asthma with a low blood eosinophil count in addition to T2-high severe asthma.22 IL-33 and thymic stromal lymphopoietin (TSLP) released from airway epithelial cells are termed ‘alarmins’ and have received attention as important cytokines that can initiate and amplify innate and adaptive immune responses to various stimulants including allergens, pollutants, viral agents, and microbial agents. Recent studies have demonstrated the roles of IL-33 and TSLP in non-T2 asthma and have suggested that these cytokines are promising therapeutic targets for non-T2 inflammation, even though both cytokines primarily drive T2 inflammation through activation of immune cells such as mast cells, eosinophils, and ILC2.23

IL-33, a member of the IL-1 family, is a cytokine predominantly secreted by structural cells at barrier tissues, such as epithelial cells, endothelial cells, and fbroblasts. IL-33 is passively released as an ‘alarmin’ upon tissue injury or necrosis. In addition to the pro-inflammatory effects of IL-33, it can act as a nuclear transcription factor.24 Thus, IL-33 is a pleiotropic cytokine with critical roles in broad-spectrum inflammatory responses including T2 and non-T2, allergic and non-allergic, and regulatory immune responses. Proteolytic maturation of full-length IL-33 by inflammatory and/or allergen proteases is an important regulatory mechanism that enhances cytokine activity.23 Moreover, cleavage by proteases from different cell types can result in differing IL-33 effects within microenvironments depending on the cell types present or those recruited to an inflammatory insult. Neutrophilic inflammatory proteases have been reported to produce the shorter form of IL-33, which has 10- to 30-fold more potent effects than full-length IL-33 on activating target cells.25, 26 In apoptotic cells, IL-33 undergoes cleavage by caspase-3 and -7 and is inactivated upon cell death, while necrotic caspase-1 produces more potent IL-33 to activate downstream pathways.27 ST2 is the functional receptor for IL-33 and is encoded by IL1RL1. ST2 has two main splice variants due to differential promoter binding: a membrane-bound form (ST2), which promotes intracellular signaling pathways including nuclear factor-κB, and a soluble form (sST2), which prevents the signaling pathways. IL-33 exerts its cytokine effects by binding to ST2 through the formation of a heterodimer complex between ST2 and IL-1 receptor accessory protein via a transmembrane domain; this results in the activation of intracellular signaling pathways.23, 28 ST2 is expressed in various immune cells including conventional and regulatory T cells, ILC2, M2 macrophages, mast cells, eosinophils, basophils, neutrophils, natural killer cells, and iNKT cells.28 Quoc et al.18 demonstrated significantly higher expression of ST2 in the peripheral neutrophils of UA patients than in those with partially controlled or controlled asthma. In addition, under stimulation with recombinant IL-33, peripheral neutrophils isolated from asthma patients showed increased expression of MPO and phosphorylation of ERK and MAPK, while those stimulated with TSLP did not.18 Taken together, these findings indicate that IL-33, a versatile cytokine, contributes to the pathobiological heterogeneity of asthma through binding to sST2 as well as ST2 in various immune cells. Given that IL-33 activity varies in response to stimuli such as air pollutants, smoke, infections, or allergens, IL-33 may be an important mediator that can account for the numerous clinical phenotypes and treatable traits of asthmatic patients. Therefore, although the role of the IL-33/ST2 axis requires further clarification in both T2-high and non-T2 airway inflammation, inhibiting the IL-33/ST2 pathway may be an effective therapeutic strategy for a wider spectrum of asthmatic patients. Recently, in a phase 2 trial, treatment with itepekimab, a humanized monoclonal antibody against IL-33, improved asthma control and QoL in patients with moderate-to-severe asthma.29 More interestingly, a novel biologic agent, astegolimab, which targets ST2, was effective in reducing the annualized asthma exacerbation rate and improving lung function with safety in a broad population of patients, including those with uncontrolled severe asthma and low eosinophil counts.30 Consistent with these findings, Quoc et al. 18 showed that treatment with an anti-ST2 antibody or anti-IL-33 antibody significantly suppressed airway neutrophilic inflammation and related inflammatory mediators such as MPO, SA100A9, and IL-17A, in addition to ILC3 maturation in a mouse model of neutrophilic asthma. These findings support the role of the IL-33/ST2 axis in non-T2, specifically neutrophilic inflammation in UA, and provide molecular mechanisms for the therapeutic effects of the anti-ST2 antibody (astegolimab) in low-eosinophilic severe asthma.

Despite its limitations as a small-sized single-center observational study, Quoc et al.18 deliver a hopeful and clear message: the IL-33/ST2 pathway is a promising signaling pathway to target in patients with poorly controlled asthma, as its blockade may attenuate neutrophilic inflammation in non-T2 asthma. To develop effective therapeutics for non-T2 asthma, new insights into the pathogenic heterogeneity of this disease entity are becoming increasingly important. The IL-33/ST2 pathway may be key to explaining the heterogeneous pathophysiology of asthma.