Epithelial cytokines and the inflammatory cascade

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.¹

Epithelial-derived cytokines (alarmins) are the body’s ubiquitous warning signals, acting as first reactors following infection and physical or immunological insult.² 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.^3,4

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.⁵ 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.^3,6–8 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.⁶ In particular, TSLP exerts its pleiotropic functions by binding to a high-affinity heteromeric complex composed of a thymic stromal lymphopoietin receptor (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.⁶ 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.⁶ While IL-33, TSLP, and IL-25 can play similar roles in T2 inflammation, their roles are more frequently divergent.⁹

Several cellular targets of TSLP, IL-33 and, to a lesser extent, IL-25 have been identified, including immune and non-immune cells.^6,8 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.^4,6–8,10

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).^4,10 Activated DCs present allergens to naïve CD4+ T cells, resulting in differentiation to T helper (Th)2 cells.^4,10 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.^4,10,11 These molecules activate eosinophils (predominantly driven by IL-5) and mast cells, which are the primary effector cells in allergic T2 inflammation.^4,10,11

TSLP, IL-33 and IL-25 activate ILC2s, resulting in production of IL-5 and IL-13, which leads to activation of eosinophils and non-allergic eosinophilic T2 inflammation.^4,10–14 

Beyond T2 inflammation, TSLP may also play a role in driving structural changes through activation of fibroblasts and mast cells.^4,15 In particular, human CD34⁺ progenitor-derived mast cells express TSLPR and IL-7R⍺.¹⁶ TSLP, in combination with certain cytokines (eg, IL-1β and tumor necrosis factor [TNF]-⍺), causes the release of several cytokines and chemokines from mast cells.^15–17 TSLP, in combination with IL-33, induces prostaglandin D₂ (PGD₂) production by human mast cells.¹⁸ 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.¹⁷ The structural changes mediated by mast cell and fibroblast activation ultimately lead to airway remodeling and airway hyperresponsiveness.^4,19

Further evidence suggests that TSLP, IL-33, and IL-25 may play a pivotal role beyond T2 inflammation.⁹ TSLP provides critical signals for T follicular helper cell (T_FH) differentiation,²⁰ human B-cell proliferation,²¹ and mast cell activation.¹⁵ 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.²² Mast cells, in response to IL-33, release T2 cytokines, which induce upregulation of IL-33 expression by epithelial cells in a feed-forward loop, suggesting that mast cells cooperate with epithelial cells through IL-33 signaling.²³ IL-33 may also potentiate the release of angiogenic and lymphangiogenic factors from human mast cells.²⁴ 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.⁶ IL-25 exerts a pathogenic role in allergic asthma and virus-induced exacerbations.²⁵

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^26,27
• Risk of asthma exacerbations²⁸
• Reduced lung function²⁷
• Reduced glucocorticoid response²⁹
• Exaggerated T2 response to viral infections^30–32
• Potential airway remodeling^33–35
• Airway hyperresponsiveness³⁶
• Mucus plugging^6,37

Additionally, increased expression of IL-25 is associated with potential airway remodeling,³⁸ and an exaggerated T2 response to viral infections.²⁵ More recently, TL1A, a novel epithelial cytokine, has also been shown to contribute to airway inflammation and remodeling through its effect on immune and structural cells.³⁹