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Review
. 2022 Oct 14:13:975914.
doi: 10.3389/fimmu.2022.975914. eCollection 2022.

Epithelial cell alarmin cytokines: Frontline mediators of the asthma inflammatory response

Marc Duchesne  1 , Isobel Okoye  1 , Paige Lacy  1
Affiliations
Review

Epithelial cell alarmin cytokines: Frontline mediators of the asthma inflammatory response

Marc Duchesne et al. Front Immunol. .

Abstract

The exposure of the airway epithelium to external stimuli such as allergens, microbes, and air pollution triggers the release of the alarmin cytokines IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). IL-25, IL-33 and TSLP interact with their ligands, IL-17RA, IL1RL1 and TSLPR respectively, expressed by hematopoietic and non-hematopoietic cells including dendritic cells, ILC2 cells, endothelial cells, and fibroblasts. Alarmins play key roles in driving type 2-high, and to a lesser extent type 2-low responses, in asthma. In addition, studies in which each of these three alarmins were targeted in allergen-challenged mice showed decreased chronicity of type-2 driven disease. Consequently, ascertaining the mechanism of activity of these upstream mediators has implications for understanding the outcome of targeted therapies designed to counteract their activity and alleviate downstream type 2-high and low effector responses. Furthermore, identifying the factors which shift the balance between the elicitation of type 2-high, eosinophilic asthma and type-2 low, neutrophilic-positive/negative asthma by alarmins is essential. In support of these efforts, observations from the NAVIGATOR trial imply that targeting TSLP in patients with tezepelumab results in reduced asthma exacerbations, improved lung function and control of the disease. In this review, we will discuss the mechanisms surrounding the secretion of IL-25, IL-33, and TSLP from the airway epithelium and how this influences the allergic airway cascade. We also review in detail how alarmin-receptor/co-receptor interactions modulate downstream allergic inflammation. Current strategies which target alarmins, their efficacy and inflammatory phenotype will be discussed.

Keywords: IL-25; IL-33; TSLP; allergy; tezepelumab.

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Conflict of interest statement

PL reports grants from Natural Science and Engineering Research Council of Canada, and Synergy Respiratory and Cardiac Care, and personal fees from GlaxoSmithKline Canada, AstraZeneca Canada, and Synergy Respiratory and Cardiac Care, Canada, outside this submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The secretion of alarmin cytokines in the airway epithelium may be triggered through multiple mechanisms which depend on the nature of the external insult. Asthma exacerbations can occur in response to air pollutants, allergens, and respiratory viruses. Various studies based on in vitrochallenged human bronchial epithelial cells and animal models indicate that IL-25, IL-33 and TSLP are released through cleavage of tight junctions (TJ), and necroptosis. Particulate matter and other air pollutants can trigger oxidative stress and the release of reactive oxygen and nitrogen species as well as DNA damage.
Figure 2
Figure 2
TSLP signalling pathways through JAK1 and JAK2. TSLP signaling pathways require a heterodimer of IL-7Ra and TSLP receptor (TSLPR). Interaction between TSLP and its receptor cascades in a signaling pathway through JAK1 and JAK2 which varies depending on the cell type. JAK1 and JAK 2 can activate STAT1, STAT3 and STAT5 as well as NF-kB and MAP kinases through PI3K, but all these pathways have not been fully resolved. The outcome of activation also varies with the type of cell affected, but includes upregulation of IL-6, IL-8, cell proliferation; in dendritic cells, activation by TSLP causes their migration and maturation to a Th2 phenotype.
Figure 3
Figure 3
IL-25 signalling pathways through Act1. The IL-17E/IL-25 signaling pathway requires a heterodimer of IL-17RA and IL-17RB which allows interactions with Act1. Act1 recruits TRAF4 and TRAF6 which activates gene upregulation through NF-kB. SMURF2 removes the inhibitory effects of DAZAP2 which allows upregulation through MAP kinases and induces JAK2 to signal through STAT5 for IL-4, IL-9 and IL-13. The IL-25 pathways available represent the resolved pathways in T cell and airway epithelial cells, but IL-25 receptors are also found on mast cells, eosinophils, basophils, and other immune cells.
Figure 4
Figure 4
IL-33 signalling pathways through MyD88. The IL-33 signaling pathway requires a heterodimer of ST2 and IL-1 receptor accessory protein (IL- 1RAcP) to activate and signal through MyD88. If IL-33 avoids binding to soluble ST2 decoys, it signals through MyD88 to interact with IRAK1 and IRAK4, which in turns activate TRAF6 and leads to NF-kB and AP-1 gene upregulation of IL-5, IL-13 and MCP-1. AP-1 is also able to activate independently of MyD88 through an undiscovered pathway involving MAP kinases.
Figure 5
Figure 5
TSLP isoforms. TSLP has two isoforms covering two distinct roles: sfTSLP (63 amino acids) for homeostasis and lf TSLP (159 amino acids) for inflammatory responses. Each isoform is under the control of different promoter regions directed by distinct pathways, with the vitamin D receptor/retinoid X receptor pathway specific for sfTSLP expression and the AP-1/NF-kB pathway for lfTSLP. Both isoforms share the same Cterminus amino acid sequence but have distinct N-terminus sequences.
Figure 6
Figure 6
Membrane-anchored ST2/soluble ST2 isoforms functional differences in role and expression. Membrane-anchored ST2 (ST2) expression is controlled by the distal promoter region through the promoters GATA1, GATA2 and PU.1. ST2 comprises the functional receptor in the IL-33/ST2 signaling pathway. Soluble ST2 (sST2) expression is controlled by the proximal promoter region. Its promoters remain to be elucidated and the isoform share the same extracellular domain which makes sST2 a competitive inhibitor of ST2 in the IL-33/ST2 signaling pathway.
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