Epithelial cytokines and the inflammatory cascade

Epithelial cytokines play upstream and downstream roles in regulating immune responses in asthma.1,2

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Epithelial cytokines (TSLP, IL-33, IL-25) are released in response to triggers, initiating a cascade of immune responses that drive clinical features of asthma.1–5  

Epithelial cytokines are rapidly released from the airway epithelium

The epithelium is a key component of the innate immune system. As described in the Role of the epithelium in asthma module, the epithelium provides a physical and immune-modulatory barrier acting as the first line of defence against environmental agents.6 

Professor Gianni Marone discusses epithelial cytokines.

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Epithelial-derived cytokines (alarmins) are the body’s ubiquitous warning signals acting as first reactors following infection and physical or immunological insult.7 Epithelial-derived cytokines (thymic stromal lymphopoietin [TSLP], interleukin [IL]-33 and IL-25) are released by activated epithelial cells in response to injury or immunological insult.2,5  

The mechanism of epithelial-cytokine release differs from the production of traditional cytokines, which are secreted by a wide-range of immune cells in response to inflammation and infection.8 In asthma, epithelial-derived cytokines, produced by both immune and non-immune cells, are released in response to a variety of triggers present at the airway epithelium, such as pathogens, cytokines, aeroallergens, mechanical injury and air pollutants.1–4 Specifically, TSLP expression and release from epithelial cells is increased in response to a broad array of stimuli, including mechanical injury, infection, inflammatory cytokines and fungi.1,4,9 However, the activity of IL-33 is regulated both by its localisation within the cell and by proteolytic cleavage.1 Although IL-33 lacks a signal sequence required for conventional secretory pathways, it can be released as an 'alarmin' in response to cellular injury or stress.10,11 

TSLP, IL-33 and IL-25 (also known as IL-17E)1 have a pleiotropic role in promoting the development of inflammation in patients with asthma by activating specific receptors on a variety of immune and non-immune cells.1 In particular, TSLP exerts its pleiotropic functions by binding to a high affinity heteromeric complex composed of TSLPR chain and IL-7R⍺.4

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Multiple inflammatory pathways infographic
Multiple inflammatory pathways are activated following release of epithelial cytokines from the epithelium

The inflammatory cascade in asthma: role of epithelial cytokines  

Once released from the epithelium, epithelial cytokines can activate and/or modulate innate and adaptive immune responses in overlapping but distinct ways.1,2 The specificity of IL-33, TSLP and IL-25 in the modulation of Type 2 (T2) inflammation is mediated by the selective expression of their different receptors on immune cells.1 While IL-33, TSLP and IL-25 can play similar roles in T2 inflammation their roles are more frequently divergent.12 

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Graph showing individual and combined impact of epithelial cytokines
TSLP, IL-33, and IL-25 have distinct but overlapping roles in activating the innate and adaptive immune responses

Several cellular targets of TSLP, IL-33 and, to a lesser extent, IL-25 have been identified, including immune and non-immune cells.1,4 The activation of these cellular targets by epithelial cytokines can cause production of several downstream cytokines (eg IL-5, IL-13 and IL-4), leading to T2 inflammation.1,3–5,13

TSLP, IL-33 and, to a lesser extent, IL-25 have a large number of cellular targets.1  IL-33 targets myeloid dendritic cells, CD4+ T cells, CD8+ T cells, regulatory T cells, natural killer T cells, mast cells, macrophages, B cells, eosinophils, basophils, neutrophils, type 2 innate lymphoid cells (ILC2s), airway epithelium and fibroblasts.1 TSLP targets myeloid dendritic cells, CD4+ T cells, CD8+ T cells, regulatory T cells, natural killer T cells, B cells, mast cells, monocytes, eosinophils, basophils, ILC2s and the airway epithelium.1  IL-25 targets ILC2s, CD4+ T cells, invariant natural killer T cells, airway epithelial cells and fibroblasts.1

Allergic eosinophilic (T2) inflammation, driven by allergen exposure, induces the release of epithelial cytokines (TSLP, IL-33 and IL-25), which can activate dendritic cells (DCs).5,13 Activated DCs present allergens to naïve CD4+ T cells resulting in differentiation to Th2 cells.5,13 Th2 cells, in collaboration with activated basophils, are a major source of IL-4, IL-5 and IL-13, which induce immunoglobulin (Ig)E class switching in B cells.5,13,14 These molecules activate eosinophils (predominantly driven by IL-5) and mast cells, which are key effector cells in allergic T2 inflammation.5,13,14 Login to access the ‘Epithelial cytokine inflammatory pathways’ downloadable asset for a visual representation of this complex pathway.

TSLP, IL-33 and IL-25 activate ILC2s resulting in production of IL-5 and IL-13; leading to activation of eosinophils and non-allergic airway inflammation.5,13–17   

Beyond T2 inflammation, TSLP may play a role in driving structural changes through activation of fibroblasts and mast cells.5,18 In particular, human CD34+ progenitor-derived mast cells express TSLPR and IL-7R⍺.19 TSLP, in combination with certain cytokines (eg IL-1β and tumor necrosis factor [TNF]-α), causes the release of several cytokines and chemokines from mast cells.18–20 TSLP, in combination with IL-33, induces prostaglandin D2 (PGD2) production by human mast cells.21 TSLP is a survival factor for human mast cells through the activation of STAT6, providing one potential explanation for mast cell accumulation in allergic disorders.20 The structural changes mediated by mast cell and fibroblast activation ultimately lead to airway remodelling and airway hyperresponsiveness.5,22 

Further evidence suggests that TSLP, IL-33 and IL-25 may play a pivotal role beyond T2 inflammation.12 TSLP provides critical signals for T follicular helper cell (TFH) differentiation,23 human B-cell proliferation,24 and mast cell activation.18 IL-33 augments the effects of rhinovirus on the inflammatory activity of human lung vascular endothelium, which may be relevant to viral-induced asthma exacerbations.25 Mast cells, in response to IL-33, release T2 cytokines which induce upregulation of IL33 expression by epithelial cells in a feed-forward loop, suggesting that mast cells cooperate with epithelial cells through IL-33 signalling.26 IL-33 may also potentiate the release of angiogenic and lymphangiogenic factors from human mast cells.27 IL-25, which belongs to the IL-17 cytokine family, exerts its biological effects by interacting with a dimeric complex consisting of the two receptor subunits IL-17R⍺ and IL-17RB.1 IL-25 exerts a pathogenic role in allergic asthma and virus-induced exacerbations.28

Epithelial cytokines are associated with clinical features of asthma 

Multiple clinical features of asthma are associated with increased expression of TSLP and/or IL-33, including: 

  • Asthma severity29,30 

  • Risk of asthma exacerbations31  

  • Reduced lung function30 

  • Reduced glucocorticoid response32 

  • Exaggerated T2 response to viral infections9,33,34 

  • Potential airway remodelling35–37 

Additionally, increased expression of IL-25 is associated with potential airway remodelling,38 and exaggerated T2 response to viral infections.28

Click here to login to access more about the potential roles of TSLP, IL-33 and IL-25 in each of these clinical features.

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Multiple inflammatory responses in asthma inforaphic
Multiple clinical features of asthma are associated with increased expression of epithelial cytokines

Find out more about the EpiCreator – Professor Gianni Marone

References


1. Roan F, et al. J Clin Invest. 2019;129:1441–1451. 2. Bartemes KR, Kita H. Clin Immunol. 2012;143:222–235. 3. McBrien CN, Menzies-Gow A. Front Med. 2017;4:93. 4. Varricchi G, et al. Front Immunol. 2018;9:1595. 5. Gauvreau GM, et al. Expert Opin Ther Targets 2020;24:777–792. 6. Holgate ST. Immunol Rev 2011;242:205–219. 7. Yang D, et al. Immunol Rev 2017;280:41–56. 8. Lacy P, Stow JL. Blood 2011;118:9–18. 9. Kato A, et al. J Immunol 2007;179:1080–1087. 10. Kouzaki H, et al. J Immunol 2011;186:4375–4387. 11. Kakkar R, et al. J Biol Chem 2012;287:6941–6948. 12. Porsbjerg CM, et al. Eur Respir J 2020;56:2000260. 13. Brusselle GG, et al. Nat Med 2013;19:977–979. 14. Lambrecht BN, Hammad H. Nat Immunol 2015;16:45–56. 15. Brusselle G, Bracke K. Ann Am Thorac Soc 2014;11:S322–S328. 16. Halim TYF, et al. Immunity 2012;36:451–463. 17. Martin NT, Martin MU. Nat Immunol 2016;17:122–131. 18. Kaur D, et al. Chest 2012;142:76–85. 19. Allakhverdi Z, et al. J Exp Med 2007;204:253–258. 20. Han N-R, et al. J Invest Dermatol 2014;134:2521–2530. 21. Buchheit KM, et al. J Allergy Clin Immunol 2016;137:1566–1576. 22. Ishmael FT. J Am Osteopath Assoc 2011;111:S11–S17. 23. Pattarini L, et al. J Exp Med 2017;214:1529–1546. 24. Milford T-AM, et al. Eur J Immunol 2016;46:2155–2161. 25. Gajewski A, et al. Allergy 2021;76:2282–2285. 26. Altman MC, et al. J Clin Invest 2019;129:4979–4991. 27. Cristinziano L, et al. Cells 2021;10:145. 28. Beale J, et al. Sci Transl Med 2014;6:256ra134. 29. Shikotra A, et al. J Allergy Clin Immunol 2012;129:104–111. 30. Li Y, et al. J Immunol 2018;200:2253–2262. 31. Ko H-K, et al. Sci Rep 2021;11:8425. 32. Liu S, et al. J Allergy Clin Immunol 2018;141:257–268. 33. Lee H-C, et al. J Allergy Clin Immunol 2012;130:1187–1196. 34. Uller L, et al. Thorax 2010;65:626–632. 35. Cao L, et al. Exp Lung Res 2018;44:288–301. 36. Wu J, et al. Cell Biochem Funct 2013;31:496–503. 37. Guo Z, et al. J Asthma 2014;51:863–869. 38. Cheng D, et al. Am J Respir Crit Care Med 2014;190:639–648. 

Read next: Find out more about airway hyperresponsiveness

To learn more about airway hyperresponsiveness, visit the Airway Hyperresponsiveness in Asthma page.

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