Editors' ChoiceAsthma

Target practice in severe asthma

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Science Translational Medicine  29 Mar 2017:
Vol. 9, Issue 383, eaan0769
DOI: 10.1126/scitranslmed.aan0769

Abstract

The NLRP3 inflammasome/caspase-1/IL-1β axis may be a therapeutic target in severe steroid-resistant asthma.

Severe steroid resistant (SSR) asthma represents a major unmet clinical need. Therapies to treat these patients are lacking, leaving them with a high disease burden. An inadequate understanding of the mechanisms underlying SSR asthma pathogenesis is likely to blame for the lack of therapeutic advances. Whereas mild steroid–sensitive asthma is associated with eosinophilic and T helper 2 (TH2) inflammation, in SSR asthma TH1/TH17 and neutrophilic inflammation may predominate. Recognizing how to target this inflammation in SSR asthma may be the key to improved treatments.

Kim et al. focus on the nucleotide-binding oligomerization domain–like receptor family, pyrin domain–containing (NLRP)3 inflammasome signaling axis as a potential mediator of SSR asthma pathogenesis. Activation of the NLRP3 inflammasome can occur in response to pathogen or host-related stimuli. This activation triggers the cleavage of pro-caspase-1 and subsequently pro-interleukin-1β (IL-1β) and pro-IL-18 into the proinflammatory cytokines IL-1β and IL-18. IL-1β has been implicated in multiple inflammatory disorders, including severe asthma, because it may trigger neutrophilic inflammation.

Kim et al. examined the NLRP3 inflammasome/caspase-1/IL-1β axis in two murine models of SSR asthma, first inducing allergic airway disease using ovalbumin challenge, then using Chlamydia or Haemophilus respiratory infections to induce steroid-resistant inflammation. Not only were NLRP3, caspase-1, and IL-1β induced in these models, but targeting them therapeutically with MCC950 (an NLRP3 inhibitor), Ac-YVAD-cho (a caspase-1 inhibitor), or a neutralizing anti–IL-1β antibody reduced the associated neutrophilic inflammation and airway hyper-responsiveness. Conversely, IL-1β administration recapitulated the infection-induced steroid resistant inflammation in a murine model. The authors then showed that increased NLRP3 and IL-1β sputum gene expression was strongly associated with increasing asthma severity in humans, suggesting that the NLRP3 inflammasome is important in human disease as well.

Therapeutic targeting of this pathway must proceed with caution because some aspects of it may be crucial for fighting infection. Furthermore, it is unclear where along the inflammasome/caspase-1/IL-1β/neutrophilic inflammation axis should be targeted for the best efficacy with the least side effects. However, this study provides another step toward finding therapies that may reverse steroid-resistant inflammation in severe asthma.

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