It is estimated that between 5 and 10% of individuals with asthma suffer from a disease that could be classified as severe, and it is this population that represents the major challenge to the medical profession, because they experience the greatest morbidity and require the greatest degree of health care with associated costs. Accordingly, development of therapeutic strategies for treatment of severe steroid-resistant asthma (SRA) now appropriately dominates the asthma landscape. It is clear that severe asthma represents a heterogeneous disease rather than manifesting as a homogeneous pathology and presentation (1). Thus, a shift in diagnostic focus away from the patient characteristics and toward the underlying pathology and drivers of disease represents a more rational strategy to identify phenotype-specific treatment regimens to match the complexity of disease (2). Critically, the molecular mechanisms that promote these distinct clinical phenotypes are not well understood. Recently, there has become a sharper focus on a problematic subgroup of patients with severe asthma presenting with steroid-resistant, neutrophilic inflammation, and these patients represent a major unmet need in asthma management (3), because they do not respond to traditional therapy and may not meet criteria for the newer biologics directed at the Th2 pathways. To understand the mechanisms driving pathology of asthma and test therapeutic potential of intervention strategies, it is critical to have preclinical animal models that display the complexity and heterogeneity of the clinical disease and reflect the specific pathology we are seeking to target. In this edition of the Journal, Kim and colleagues (pp. 283–297) use robust animal models and paired clinical studies to demonstrate the importance of nucleotide-binding domain and leucine-rich repeat–containing protein 3 (NLRP3) inflammasome–mediated IL-1β production in driving the pathology of SRA and highlight that intervention of this pathway offers clear therapeutic potential (4).

Experimental in vivo models of asthma have traditionally focused on allergic inflammation induced by Th2 pathways and have therefore relied on Th2 skewing adjuvants. However, more recently there have been efforts to generate models that are resistant to steroids and thus have incorporated other aspects of the immune system. Use of complex allergens that feature protease activity, pathogen products such as pathogen-associated molecular patterns, or proteins like chitins, or via the combination of allergens and pathogen, results in the recruitment of a more mixed granulocytic infiltrate that incorporates neutrophils as well as eosinophils and a more diverse cytokine repertoire (1). In the current issue, Kim and colleagues use a complex model of allergen and infection, which is resistant to steroid treatment, to unravel novel molecular mechanisms underlying severe asthma (4). Critically, they have used change in lung function as a readout throughout. This is of vital importance, as this is the defining characteristic of the disease—regardless of the cellular pathology—and improvement in lung function is of paramount importance to patients.

Although there is increasing evidence implicating NLRP3 inflammasome activation and IL-1β release in severe neutrophilic asthma (5, 6), this study is the first to clearly dissect the significance of this pathway in defining SRA pathology. Kim and colleagues demonstrate that infection of mice with either Chlamydia or Haemophilus after allergen sensitization and challenge resulted in steroid-resistant disease characterized by neutrophilic inflammation and an increase in expression and activation of the NLRP3/IL-1β pathway (4). Further analysis of clinical samples corroborated the notion that the NLRP3/IL-1β pathway was instrumental in SRA, with sputum NLRP3 and IL-1β expression correlating with neutrophilia, severity of disease, and steroid resistance. The authors go on to rigorously and convincingly demonstrate the importance of this pathway in driving SRA, with neutralization of IL-1β and inhibition of caspase-1 or NLRP3 all consistently reducing IL-1β, neutrophilic inflammation, and airway hyperresponsiveness (AHR). Supportive of an IL-1β–neutrophil axis in driving SRA, repeated intranasal administration of recombinant IL-1β to naive mice was sufficient to promote a steroid-resistant neutrophilia and AHR. Furthermore, recombinant IL-1β administration to mice with an eosinophil-dominated, steroid-sensitive allergic disease promoted a neutrophilic inflammation and AHR that was steroid resistant.

As convincing and intriguing as the studies detailed in this manuscript are, as always there remain questions to be answered. An NLRP3/IL-1β response is clearly associated with steroid-resistant neutrophilia and AHR, but what are the series of events and mechanisms that define this pathway? Does the elevated IL-1β promote an augmented neutrophilic response that subsequently underlies the AHR, or are the neutrophilia and AHR two mutually exclusive downstream sequelae of the IL-1β? The authors demonstrate that neutrophil depletion in naive mice administered recombinant IL-1β abrogates the AHR, suggestive that it is the former. However, is this series of events as absolute in the infection-induced SRA models as in naive mice, because a pan-caspase inhibitor administered in the SRA model partially reduces IL-1β and AHR without affecting neutrophilic infiltrate? Future studies might also probe the manner by which IL-1β promotes the neutrophilic inflammation within the SRA model and how precisely the IL-1β/neutrophilia drives the steroid-resistant AHR.

The authors demonstrate that the elevated NLRP3 expression in their SRA models is restricted to the airway epithelium and infiltrating leukocytes, but which specific populations of leukocytes are the prominent producers of IL-1β in this system? NLRP3 inflammasome-mediated IL-1β release is a prominent feature of macrophages (7), which are also elevated in the Chlamydia SRA model, but neutrophils themselves have also been reported to release IL-1β via this pathway (8, 9). In the current study, IL-1β expression correlates with neutrophilia in both murine models and clinical samples, but is this solely because the IL-1β is driving the neutrophilia or are neutrophils themselves also producing IL-1β, thereby promoting a vicious circle of inflammation? Given the abundance of neutrophils in the SRA models, it is pertinent that neutrophil-derived proteases can also activate any extracellular pro–IL-1β and enhance and amplify the initial caspase-1–mediated activation (10), and thus may further perpetuate IL-1β–driven inflammation. Furthermore, what are the signals that are driving both the expression and activation of the NLRP3 inflammasome complex within these infection-induced SRA models? It would be interesting to determine whether a similar mechanistic pathway underlies the severe pathology induced by viral exacerbations of asthma. It is estimated that the majority of exacerbations are induced by common respiratory viruses such as rhinovirus or respiratory syncytial virus—particularly in children. Although the immune response to viruses and bacteria are different, both types result in recruitment of neutrophils, and thus similar pathways may operate to induce pathology.

Severe, steroid-resistant, neutrophilic asthma remains a clear unmet need in asthma management, and thus these studies detailing the therapeutic potential of targeting the NLRPR3/IL-1β pathway are of clear translational interest. Kim and colleagues demonstrate the therapeutic efficacy of targeting the NLRP3 inflammasome pathway at various levels, be it inhibition of caspase-1 or NLRP3 itself or IL-1β antagonism (4). As with all antiinflammatory strategies, there is always an inherent risk of compromising host defense, and yet adverse infectious events are seemingly rare in patients in whom IL-1β signaling has been perturbed (11). Nonetheless, given the specific involvement of the NLRP3 inflammasome in driving SRA, it may be prudent to assess the therapeutic potential of selective NLRP3 inhibitors, such as MCC950, in the clinic rather than strategies that will affect global IL-1β production from all inflammasome complexes. Regardless, these exciting studies by Kim and colleagues highlight a clear rationale to reduce IL-1β availability to ameliorate neutrophilic SRA (4).

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