Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites

Abstract

There is compelling evidence that epithelial cells (ECs) at mucosal surfaces, beyond their role in creating a physical barrier, are integral components of innate and adaptive immunity. The capacity of these cells to license the functions of specific immune cell populations in the airway and gastrointestinal tract offers the prospect of novel therapeutic strategies to target multiple inflammatory diseases in which barrier immunity is dysregulated. In this review, we discuss the critical functions of EC-derived thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33 in the development and regulation of T-helper 2 (Th2) cytokine-dependent immune responses. We first highlight recent data that have provided new insights into the factors that control expression of this triad of cytokines and their receptors. In addition, we review their proinflammatory and immunoregulatory functions in models of mucosal infection and inflammation. Lastly, we discuss new findings indicating that despite their diverse structural features and differential expression of their receptors, TSLP, IL-25, and IL-33 cross-regulate one another and share overlapping properties that influence Th2 cytokine-dependent responses at mucosal sites.

Figure 1. Epithelial cells as a source of TSLP, IL-25, and IL-33 in vivo

TSLP expression is induced following helminth infection, tissue damage, and exposure to T_H2 and pro-inflammatory cytokines (A). Nippostrongylus-infection and exposure to common allergens upregulates expression of IL-25 (B). To date only Trichuris infection has been shown to upregulated expression of IL-33 in intestinal ECs (C). EC, epithelial cell; IL, interleukin; TSLP, thymic stromal lymphopoietin.

Figure 2. Downstream signaling pathways activated following receptor ligation by TSLP, IL-25, and IL-33

Binding of TSLP to its receptor complex results in the phosphorylation of STAT-5 and STAT-3, although the involvement of a specific JAK has not been elucidated (A). IL-25-mediated activation of NF-κB is dependent on TRAF-6, whereas activation of the MAPK pathway does not require TRAF-6 (B). TRAF-6 and MyD88 are both required for intact IL-33 signaling. Additionally, IL-33 can activate both the MAPK and JNK pathways (C). STAT, signal transducers and activators of transcription; JAK, Janus kinase; MAPK, mitogen-acitvated protein kinase; TRAF, TNF receptor associated factor.

Figure 3. Cross-regulation between TSLP, IL-25, and IL-33

Target cell populations are indicated including a summary of the effects of each of these cytokines on that cell lineage.