Regulation of Airway Epithelial-Derived Alarmins in Asthma: Perspectives for Therapeutic Targets

Abstract

Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients.

Keywords: airway epithelium; alarmin cytokines; allergies; asthma; biologic therapy; pollutants; respiratory infections.

Figure 1

The airway epithelial production of alarmins in response to inhaled triggers. (A) Allergen triggers like pollen and HDM activate PRRs like TLR2 and 4 [137,138,139]. Protease allergens, including Der p 1 and 9 found in HDM, have the ability to directly disrupt and degrade tight junction proteins and can also trigger PAR2 [137,143,144]. Other motifs, like β-glucans and microbial patterns, can be detected by PRRs like dectin-1 and NOD1, respectively [137,140,142,145,146]. Allergen exposure can also induce the release of ATP into the extracellular space which, in turn, induces the influx of Ca²⁺ via P2 purinergic receptors [147]. TRP channels like TRPA1 and TRPV1 are also implicated in allergen-mediated Ca²⁺ influx, along with the release of ATP [148,149]. Allergen triggers via these receptors and channels induce the production of TSLP, IL-33, IL-25 and IL-1α [140,141,142,147,148,149,150,151,152,153]. (B) Viral pathogens are primary detected by intracellular TLRs located in endosomes, including TLR3 and TLR7, which can recognize viral double-strand (ds) RNA and single-strand (ss) RNA, respectively. The further detection of viral nucleic acids is mediated by cytosolic RLRs like RIG-1 and MDA-5 [154]. Bacterial pathogens are typically recognized by TLR2 and 4 through various microbial PAMPs including peptidoglycan and LPS [155]. NLRs like NOD1 and 2, along with NLR inflammasomes, work to detect bacterial pathogens intracellularly [155,156]. These inhaled respiratory pathogens activate these receptors, inducing the production of TSLP, IL-33, IL-25 and HMGB1 [156,157,158,159,160,161]. (C) Environmental pollutants like DEPs activate PAR2, resulting in the production of MMP-1 through increased intracellular Ca²⁺ concentrations via TRPV4 activation [162]. DEPs can intracellularly activate aryl hydrocarbon receptor (Ahr) and also penetrate intracellularly, causing the disruption of epithelial junctional proteins [19,163]. PM2.5 is another type of environmental pollutant that is detected by PRRs like TLR2 and 4 through microbial patterns [164,165]. TRP channels like TRPA1 and TRPV1 are also implicated in working cooperatively with PRRs like TLR4 to mediate PM2.5-induced pathology [166]. Overall, environmental pollutants induce the production of TSLP, IL-33, IL-25, IL-1α and HMGB1 through the activation of these receptors and channels [19,167,168,169]. This release of alarmins, specifically TSLP, is crucial for the development and regulation of ILC2 and Th2 proliferation, known as the ILC2-DC-Th2 axis [31]. Briefly, these alarmins can individually or synergistically activate ILC2, resulting in the production of T2 cytokines IL-4, IL-5 and IL-13 [32]. TSLP mediates the activation of dendritic cells and upregulates the expression of OX40L, which subsequently are required for the maturation of naïve T-cells into Th2 cells [19]. The downstream production of IL-5 promotes the recruitment of and production of eosinophils [170]. IL-4, on the other hand, promotes the isotype switch and secretion of IgE by B cells. This enhances the IgE-mediated immune response by upregulating high-affinity FcεRI on mast cells and basophils [94]. The degranulation of activated mast cells and basophils results in the release other inflammatory mediators, like histamine, causing bronchoconstriction, and pro-inflammatory cytokines that further drive airway inflammation. This figure was created with BioRender.com (accessed on 7 October 2024).