Epithelial cytokines and the inflammatory cascade

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

Article
 

Epithelial cytokines (eg, TSLP) are released in response to triggers, initiating a cascade of immune responses that drive clinical features of asthma.1–4

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 defense against environmental agents.5 

Professor Gianni Marone discusses epithelial cytokines.

Watch Video

 

Epithelial-derived cytokines (alarmins) are the body’s ubiquitous warning signals acting as first reactors following infection and physical or immunological insult.6 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.2,7 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 TSLP, IL-33, and, to a lesser extent, IL-25 (also known as IL-17E), 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 a TSLPR chain and IL-7Rα.4

 

Image
The epithelium is a key source of inflammation infographic
Multiple inflammatory pathways are activated following release of TSLP 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 The specificity of IL-33, TSLP and IL-25 in the modulation of allergic 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.9

 

Image
Distinct but overlapping roles infographic
TSLP, IL-33, and IL-25 have distinct but overlapping roles in activating the innate and adaptive immune responses

Several cellular targets of TSLP have been identified, including immune and non-immune cells.1,4 The activation of these cellular targets by TSLP can cause production of several downstream cytokines (eg, IL-5, IL-13, and IL-4), leading to T2 and non-T2 allergic inflammation.1,3,4,7,10

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.

Allergic (T2) inflammation, driven by allergen exposure, induces the release of TSLP, which can activate dendritic cells (DCs).7,10 Activated DCs present allergens to naïve CD4+ T cells, resulting in differentiation to T helper (Th)2 cells.7,10 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.7,10,11 These molecules activate eosinophils (predominantly driven by IL-5) and mast cells, which are the primary effector cells in allergic T2 inflammation.7,10,11 Access the ‘Epithelial cytokine inflammatory pathways’ downloadable asset for a visual representation of this complex pathway.

TSLP also activates ILC2s, resulting in production of IL-5 and IL-13, which leads to activation of eosinophils and non-allergic airway inflammation.7,10–12 

Beyond T2 inflammation, TSLP may also play a role in driving structural changes through activation of fibroblasts and mast cells,7,13 leading to airway remodeling.7,14 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.13,15,16 TSLP, in combination with IL-33, induces prostaglandin D2 (PGD2) production by human mast cells.17 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.16

Further evidence suggests that TSLP may play a role beyond T2 inflammation by providing critical signals for T follicular helper cell (TFH) differentiation,18 human B-cell proliferation,19 and mast cell activation.13

 

Dr. Michael E. Wechsler describes the role of epithelial cytokines in the inflammatory asthma cascade.

Watch Video

 

Epithelial cytokines are associated with clinical features of asthma

Multiple clinical features of asthma are associated with increased expression of TSLP, including:

  • Asthma severity20,21
  • Risk of asthma exacerbations22
  • Reduced lung function21
  • Reduced glucocorticoid response23
  • Exaggerated T2 response to viral infections24-26
  • Potential airway remodeling27,28

Click here to learn more about the potential roles of TSLP and epithelial cytokines in each of these clinical features.

Image
Clinical features infographic
Multiple clinical features of asthma are associated with increased expression of TSLP

Find out more about the EpiCreator – Professor Gianni Marone

 

TSLPR, TSLP receptor chain; IL-7Rα, IL-7 receptor-α

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. Holgate ST. Immunol Rev. 2011;242:205–219. 6. Yang D, et al. Immunol Rev. 2017;280:41–56. 7. Gauvreau GM, et al. Expert Opin Ther Targets. 2020;24:777–792. 8. Lacy P, Stow JL. Blood. 2011;118:9–18. 9. Porsbjerg CM, et al. Eur Respir J. 2020;56:2000260. 10. Brusselle GG, et al. Nat Med. 2013;19:977–979. 11. Lambrecht BN, Hammad H. Nat Immunol. 2015;16:45–56. 12. Brusselle G, Bracke K. Ann Am Thorac Soc. 2014;11(Suppl. 5):S322–S328. 13. Kaur D, et al. Chest. 2012;142:76–85. 14. Ishamel FT. J Am Osteopath Assoc. 2011;111(Suppl. 7):S11-S17. 15. Allakhverdi Z, et al. J Exp Med. 2007;204:253-258. 16. Han N-R, et al. J Invest Dermatol. 2014;134:2521–2530. 17. Buchheit KM, et al. J Allergy Clin Immunol. 2016;137:1566–1576. 18. Pattarini L, et al. J Exp Med. 2017;214:1529–1546. 19. Milford T-AM, et al. Eur J Immunol. 2016;46:2155–2161. 20. Shikotra A, et al. J Allergy Clin Immunol. 2012;129:104–111. 21. Li Y, et al. J Immunol. 2018;200:2253–2262. 22. Ko H-K, et al. Sci Rep. 2021;11:8425. 23. Liu S, et al. J Allergy Clin Immunol. 2018;141:257–268. 24. Lee H-C, et al. J Allergy Clin Immunol. 2012;130:1187–1196. 25. Uller L, et al. Thorax. 2010;65:626–632. 26. Kato A, et al. J Immunol. 2007;179:1080–1087. 27. Cao L, et al. Exp Lung Res. 2018;44:288–301. 28. Wu J, et al. Cell Biochem Funct. 2013;31:496–503.

Read next: Find out more about airway hyperresponsiveness

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

RELATED RESOURCES

Like this page? We have a host of other resources available in the ‘Scientific and Resource Library’ where you can find out more.