1-Minute Summary: Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation

The concept of united airway diseases (UAD) includes allergic rhinitis (AR), chronic rhinosinusitis (CRS), and asthma, all of which share common immune-pathogenic mechanisms [1-4]. Moreover, a systemic link between upper and lower airways exists by shared molecular and inflammatory mechanisms, including overproduction of type-2 cytokines in AR, CRS, and asthma [5,6], not limited to the target organs.

There is a hypothesis that emphasizes IL-25, IL-33, and TSLP as key regulatory factors that link epithelial-mesenchymal communications and induce pathophysiological changes in the airway [1].

IL-25 is a Th2 cell-derived pro-inflammatory cytokine and a member of the IL-17 family [7]. It is rapidly released upon exposure to allergens containing protease activities, inducing allergic inflammation [8]. IL-25 has numerous responders and mediates both the innate and adaptive immune system to evoke a Th2-skewed mucosal inflammation [1].

IL-33 is a member of the IL-1 family and induces Th2 inflammation in a manner similar to IL-25 [9-11]. In the lower airway, the distinct increase in IL-33 is responsible for the development and exacerbation of airway hypersensitivity and asthma [12,13]. Moreover, IL-33 can play a role in allergic inflammation. The pathways and mechanisms of IL-33–induced airway allergy still remain ambiguous [1].

TSLP was first identified as a IL-7–like growth factor and is localized in epithelial cells, mast cells, bronchial smooth muscle cells, dendritic cells, and fibroblasts in the airway [15,16]. Endogenous triggers include pro-inflammatory cytokines, Th2-related cytokines, and IgE [16]. Upon endogenous and exogenous triggers, TSLP can exacerbate allergic inflammation via activating downstream responders, among others Th2 cells and myeloid dendritic cells [17]. TSLP is involved in the pathogenesis of inflammatory airway diseases including AR, CRS, asthma, and COPD [18].

Reciprocal interactions of IL-25, IL-33, TSLP, and other cytokines make up a complex regulatory network. They can induce type-2 responses and their synergy can further exacerbate induced inflammation. However, IL-17A, IL-1β, INFγ, and TGFβ can suppress the expression of these epithelium-derived cytokines, thus inhibiting type-2 responses (see Figure) [20-22].

hypersensitivity and asthma [12,13]. Moreover, IL-33 can play a role in allergic inflammation. The pathways and mechanisms of IL-33–induced airway allergy still remain ambiguous [1].

TSLP was first identified as a IL-7–like growth factor and is localized in epithelial cells, mast cells, bronchial smooth muscle cells, dendritic cells, and fibroblasts in the airway [15,16]. Endogenous triggers include pro-inflammatory cytokines, Th2-related cytokines, and IgE [16]. Upon endogenous and exogenous triggers, TSLP can exacerbate allergic inflammation via activating downstream responders, among others Th2 cells and myeloid dendritic cells [17]. TSLP is involved in the pathogenesis of inflammatory airway diseases including AR, CRS, asthma, and COPD [18].

Reciprocal interactions of IL-25, IL-33, TSLP, and other cytokines make up a complex regulatory network. They can induce type-2 responses and their synergy can further exacerbate induced inflammation. However, IL-17A, IL-1β, INFγ, and TGFβ can suppress the expression of these epithelium-derived cytokines, thus inhibiting type-2 responses (see Figure) [20-22].

Figure: Cytokine network and their reciprocal regulation [1]

In conclusion, TSLP, IL-25, and IL-33 are produced as the first line of defense against infections and stimulations in the airway epithelium, thus leading to potent augmentations of allergic inflammations and exerting effects as “bridges” linking innate and adaptive airway mucosal immunities [1].

 

References

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