Targeting interleukin-33 and thymic stromal lymphopoietin pathways for novel pulmonary therapeutics in asthma and COPD

Abstract

Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette smoke, and play critical roles in the activation of immune cell populations such as mast cells, eosinophils and group 2 innate lymphoid cells. Both cytokines were previously understood to primarily drive type 2 (T2) inflammation, but there is emerging evidence for a role for these alarmins to additionally mediate non-T2 inflammation, with recent clinical trial data in asthma and COPD cohorts with non-T2 inflammation providing support. Currently available treatments for both COPD and asthma provide symptomatic relief with disease control, improving lung function and reducing exacerbation rates; however, there still remains an unmet need for further improving lung function and reducing exacerbations, particularly for those not responsive to currently available treatments. The epithelial cytokines/alarmins are involved in exacerbations; biologics targeting TSLP and IL-33 have been shown to reduce exacerbations in moderate-to-severe asthma, either in a broad population or in specific subgroups, respectively. For COPD, while there is clinical evidence for IL-33 blockade impacting exacerbations in COPD, clinical data from anti-TSLP therapies is awaited. Clinical data to date support an acceptable safety profile for patients with airway diseases for both anti-IL-33 and anti-TSLP antibodies in development. We examine the roles of IL-33 and TSLP, their potential use as drug targets, and the evidence for target patient populations for COPD and asthma, together with ongoing and future trials focused on these targets.

FIGURE 1

Interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) pathways in asthma and COPD. In response to insults to the airway epithelium, the alarmins IL-33 and TSLP are released from damaged epithelial cells, although other sources of the alarmins also exist. The alarmin IL-25 (not pictured here) is also released upon epithelial damage and has shown to induce type 2 (T2) inflammation and eosinophilia. IL-33 promotes inflammation through binding to its receptor, ST2 (IL1RL1), which is present on multiple cells including neutrophils, eosinophils, macrophages, basophils and mast cells, resulting in the production of both T2 and non-T2 cytokines. Binding of IL-33 to the ST2 receptor results in activation of downstream mitogen-activated protein kinase (MAPK) and NF-κB signalling. A decoy, soluble form of the ST2 receptor acts as a negative regulator of IL-33 activity. Full-length IL-33 can undergo cleavage from different proteases (e.g. neutrophil elastase), which can produce shorter isoforms that can either enhance or reduce IL-33 activity. Cigarette smoke has been shown to shift the type of immune response to IL-33, limiting the T2 while leading to an exaggerated T1 response. TSLP has a broad immune effect, activating multiple cell types and resulting in the production of cytokines typically associated with a T2 response, while also affecting mast cells, T-helper (Th) 1 cells, and other cells that result in the production of both T2 and non-T2 cytokines. TSLP signals through its receptor, TSLPR, to activate downstream Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways with the absence of any decoy TSLPR. IL-33 and TSLP inflammatory pathways ultimately result in changes to the nonimmune components of the lung microenvironment, such as smooth muscle contraction/hyperreactivity (both), goblet cell mucus production (both), fibroblast activation (IL-33) and sensory neurons (TSLP), which contributes to the clinical symptoms and traits of asthma and COPD. Figure created using BioRender.com. IgE: immunoglobulin E; IRAK: IL-1 receptor-associated kinase; MYD88: myeloid differentiation primary response gene 88; NK: natural killer; TNF-α: tumour necrosis factor α.