Epithelial cytokines play upstream and downstream roles in regulating immune responses in asthma.1,2
Epithelial cytokines play upstream and downstream roles in regulating immune responses in asthma1,2
Further understanding of the role of epithelial cytokines in the inflammatory cascade in airway disease can provide greater insights into asthma pathophysiology and possible future intervention options, with the aim to improve patient outcomes20
IL, interleukin; T2, type 2; TSLP, thymic stromal lymphopoietin.
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 (Lausanne). 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. Brusselle GG, et al. Nat Med. 2013;19:977–979. 7. Lambrecht BN, Hammad H. Nat Immunol. 2015;16:45–56. 8. Kaur D, et al. Chest. 2012;142:76–85. 9. Kato A, et al. J Immunol. 2007;179:1080–1087. 10. Beale J, et al. Sci Transl Med. 2014;6:256ra134. 11. Shikotra A, et al. J Allergy Clin Immunol. 2012;129:104–111. 12. Li Y, et al. J Immunol. 2018;200:2253–2262. 13. Ko H-K, et al. Sci Rep. 2021;11:8425. 14. Liu S, et al. J Allergy Clin Immunol. 2018;141:257–268. 15. Lee H-C, et al. J Allergy Clin Immunol. 2012;130:1187–1196. 16. Uller L, et al. Thorax. 2010;65:626–632. 17. Cao L, et al. Exp Lung Res. 2018;44:288–301. 18. Wu J, et al. Cell Biochem Funct. 2013;31:496–503. 19. Guo Z, et al. J Asthma. 2014;51:863–869. 20. Cheng D, et al. Am J Respir Crit Care Med. 2014;190:639–648.
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
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
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
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.1
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.
Epithelial cytokines are associated with clinical features of asthma
Multiple clinical features of asthma are associated with increased expression of TSLP, including:
Click here to learn more about the potential roles of TSLP and epithelial cytokines in each of these clinical features.
Multiple clinical features of asthma are associated with increased expression of TSLP
Find out more about the EpiCreator – Professor Gianni Marone.
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TSLPR, TSLP receptor; 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.