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

Expert Name
Haiyu Hong
Expert Affiliation
Department of Otolaryngology, Allergy Center, The Fifth Affiliated Hospital of Sun Yat‐sen University, Zhuhai, China
Journal
European Journal of Allergy and Clinical Immunology

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

  1. Hong H, Liao S, Chen F, Yang Q, Wang DY. Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type-2 inflammation [published online ahead of print, 2020 Aug 1]. Allergy. 2020;10.1111/all.14526.
  2. Pfaar O, Agache I, Blay F, et al. Perspectives in allergen immunotherapy: 2019 and beyond. Allergy. 2019;74(Suppl 108):3-25.
  3. Yii A, Tay TR, Choo XN, Koh M, Tee A, Wang DY. Precision medicine in united airways disease: A “treatable traits” approach. Allergy. 2018;73(10):1964-1978.
  4. Samitas K, Carter A, Kariyawasam HH, Xanthou G. Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: The one airway concept revisited. Allergy. 2018;73(5):993-1002.
  5. Campo P, Eguiluz-Gracia I, Plaza-Serón MC, et al. Bronchial asthma triggered by house dust mites in patients with local allergic rhinitis. Allergy. 2019;74(8):1502-1510.
  6. Rondon C, Campo P, Eguiluz-Gracia I, et al. Local allergic rhinitis is an independent rhinitis phenotype: The results of a 10-year follow-up study. Allergy. 2018;73(2):470-478.
  7. Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001;15(6):985-995.
  8. Kouzaki H, Tojima I, Kita H, Shimizu T. Transcription of interleukin-25 ind extracellular release of the protein is regulated by allergen proteases in airway epithelial cells. Am J Respir Cell Mol Biol. 2013;49(5):741-750.
  9. Ihara F, Sakurai D, Yonekura S, et al. Identification of specifically reduced Th2 cell subsets in allergic rhinitis patients after sublingual immunotherapy. Allergy. 2018;73(9):1823-1832.
  10. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479-490.
  11. Zhou X, Wei T, Cox CW, Jiang Y, Roche WR, Walls AF. Mast cell chymase impairs bronchial epithelium integrity by degrading cell junction molecules of epithelial cells. Allergy. 2019;74(7):1266-1276.
  12. Hesse L, van Ieperen N, Habraken C, et al. Subcutaneous immunotherapy with purified Der p1 and 2 suppresses type 2 immunity in a murine asthma model. Allergy. 2018;73(4):862-874.
  13. Kaur D, Gomez E, Doe C, et al. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk. Allergy. 2015;70(5):556-567.
  14. Kim EH, Kim JH, Samivel R, et al. Intralymphatic treatment of flagellin-ovalbumin mixture reduced allergic inflammation in murine model of allergic rhinitis. Allergy. 2016;71(5):629-639.
  15. Chen X, Deng R, Chi W, et al. IL-27 signaling deficiency develops Th17-enhanced Th2-dominant inflammation in murine allergic conjunctivitis model. Allergy. 2019;74(5):910-921.
  16. Takai T. TSLP expression: cellular sources, triggers, and regulatory mechanisms. Allergol Int. 2012;61(1):3-17.
  17. Maruyama N, Takai T, Kamijo S, et al. Cyclooxygenase inhibition in mice heightens adaptive- and innate-type responses against inhaled protease allergen and IL-33. Allergy. 2019;74(11):2237-2240.
  18. Chen Z-G, Zhang T-T, Li H-T, et al. Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite. PLoS One. 2013;8(1):e51268.
  19. Liao B, Cao P-P, Zeng M, et al. Interaction of thymic stromal lymphopoietin, IL-33, and their receptors in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps. Allergy. 2015;70(9):1169-1180.
  20. Xu G, Zhang L, Wang DY, et al. Opposing roles of IL-17A and IL-25 in the regulation of TSLP production in human nasal epithelial cells. Allergy. 2010;65(5):581-589.
  21. Ogasawara N, Klingler AI, Tan BK, et al. Epithelial activators of type 2 inflammation: Elevation of thymic stromal lymphopoietin, but not IL-25 or IL-33, in chronic rhinosinusitis with nasal polyps in Chicago, Illinois. Allergy. 2018;73(11):2251-2254.
  22. Tan H-T, Hagner S, Ruchti F, et al. Tight junction, mucin, and inflammasome-related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice. Allergy. 2019;74(2):294-307.

 

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