Alternative splicing of interleukin-33 and type 2 inflammation in asthma

Abstract

Type 2 inflammation occurs in a large subgroup of asthmatics, and novel cytokine-directed therapies are being developed to treat this population. In mouse models, interleukin-33 (IL-33) activates lung resident innate lymphoid type 2 cells (ILC2s) to initiate airway type 2 inflammation. In human asthma, which is chronic and difficult to model, the role of IL-33 and the target cells responsible for persistent type 2 inflammation remain undefined. Full-length IL-33 is a nuclear protein and may function as an "alarmin" during cell death, a process that is uncommon in chronic stable asthma. We demonstrate a previously unidentified mechanism of IL-33 activity that involves alternative transcript splicing, which may operate in stable asthma. In human airway epithelial cells, alternative splicing of the IL-33 transcript is consistently present, and the deletion of exons 3 and 4 (Δ exon 3,4) confers cytoplasmic localization and facilitates extracellular secretion, while retaining signaling capacity. In nonexacerbating asthmatics, the expression of Δ exon 3,4 is strongly associated with airway type 2 inflammation, whereas full-length IL-33 is not. To further define the extracellular role of IL-33 in stable asthma, we sought to determine the cellular targets of its activity. Comprehensive flow cytometry and RNA sequencing of sputum cells suggest basophils and mast cells, not ILC2s, are the cellular sources of type 2 cytokines in chronic asthma. We conclude that IL-33 isoforms activate basophils and mast cells to drive type 2 inflammation in chronic stable asthma, and novel IL-33 inhibitors will need to block all biologically active isoforms.interleukin-33 | alternative splicing | type 2 inflammation | asthma | basophils

Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias

“…Our previous studies showed accumulation of mast cells in the airways of severe asthmatics (31), and more recently, they were detected in the sputum of subjects with persistent asthma (32). Their recruitment to ASMs in the airways of asthmatics was shown to require CXCR3 expressed by the cells (17).…”

“…CXCL10 mRNA levels were estimated in BAL cells from patients with mild to moderate (n = 18) or SA (n = 17) and from healthy controls (n = 12) ( 32], respectively, P = 0.02). This increased level was strongly driven by a subgroup of approximately 50% of SA patients with markedly elevated CXCL10 mRNA levels.…”

The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment

“…Moreover, alternative splicing-mediated deletion of exon 3 and 4 of IL33 transcripts confers cytoplasmic localization of IL-33 proteins, which facilitates its extracellular secretion from airway epithelial cells of asthmatic patients. Importantly, this isoform of IL-33 was shown to retain its ability to signal through ST2 (122). Thus, it is conceivable that such IL-33 isoforms are also preferentially produced by tumor cells (or cells in the tumor microenvironment), a hypothesis that remains to be addressed.…”

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung

“…In our hands, treatment with r-sST2 to block IL-33 at the time of sensitization completely abolished eosinophilic airway inflammation, Th2-cell-associated cytokine production, and GCM particularly when administered in the period of maximal lung alveolarization. Consistently, polymorphisms in IL1RL1, coding for ST2 (IL-33R), as well as the IL33 gene itself have been found associated with asthma and blood eosinophil counts, particularly in childhood asthma (Bøn-nelykke et al, 2014;Castanhinha et al, 2015;Gordon et al, 2016;Moffatt et al, 2010;Saglani et al, 2013;Savenije et al, 2011;Torgerson et al, 2011;Traister et al, 2015). In asthmatics, polymorphisms in IL1RL1 also control the relative abundance of the cell-bound IL-33R (ST2L) versus the soluble IL-33 receptor (sST2), that acts as a decoy receptor and antagonist of the IL-33-IL-33R axis (Grotenboer et al, 2013;Traister et al, 2015).…”