Epithelial cytokines and the inflammatory cascade

Epithelial cytokines are rapidly released from the airway epithelium

The epithelium is a key orchestrator of the innate immune system. As described in 'The role of the epithelium in asthma', the epithelium provides a physical and immune-modulatory barrier acting as the first line of defence against environmental agents.³ 

Epithelial-derived cytokines (alarmins) are the body’s ubiquitous warning signals, acting as first reactors following infection and physical or immunological insult.⁴ 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.⁶ 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.^1,2,7,8 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.^1,8,9 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⍺.⁸

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 

Several cellular targets of TSLP, IL-33 and, to a lesser extent, IL-25 have been identified, including immune and non-immune cells.^1,8 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.^1,5,7,8,13

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  Click here 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 severity^29,30 
• Risk of asthma exacerbations³¹  
• Reduced lung function³⁰ 
• Reduced glucocorticoid response³² 
• Exaggerated T2 response to viral infections^9,33,34 
• Potential airway remodelling^35–37 

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