Dynamic role of epithelium-derived cytokines in asthma

Abstract

Asthma is an inflammatory disorder of the airways, characterized by infiltration of mast cells, eosinophils, and Th2-type CD4+ T cells in the airway wall. Airway epithelium constitutes the first line of interaction with our atmospheric environment. The protective barrier function of the airway epithelium is likely impaired in asthma. Furthermore, recent studies suggest critical immunogenic and immunomodulatory functions of airway epithelium. In particular, a triad of cytokines, including IL-25, IL-33 and TSLP, is produced and released by airway epithelial cells in response to various environmental and microbial stimuli or by cellular damage. These cytokines induce and promote Th2-type airway inflammation and cause remodeling and pathological changes in the airway walls, suggesting their pivotal roles in the pathophysiology of asthma. Thus, the airway epithelium can no longer be regarded as a mere structural barrier, but must be considered an active player in the pathogenesis of asthma and other allergic disorders.

Figure 1

Interplay between epithelium, immune cells and epithelium-derived cytokines in asthma. Environmental insults (allergens/proteases, microbes, viruses, etc.) stimulate the release of IL-25, IL-33 and TSLP from airway epithelial cells. This triad of cytokines mediates both overlapping and unique effects on immune and structural cells in the airways. They activate DCs, basophils, mast cells, eosinophils, differentiated Th2 cells and NKT cells and drive Th2-type inflammation. Additionally, TSLP induces DC maturation (i.e. upregulation of MHC II and co-stimulatory molecules) capable of polarizing naïve CD4+ cells to the Th2-type. IL-25 and IL-33 induce Th2 cytokine production by innate lymphoid cells and drive macrophages to release IL-13. Th2 cytokines elicit multiple effects on airway tissues, including remodeling, fibrosis and proliferation of smooth muscle cells. Epithelium-derived cytokines, IL-25, IL-33 and TSLP, and the products of Th2-type immune responses provide a positive feedback to airway epithelial cells by enhancing production of mucus and matrix proteins and by stimulating production of cytokines, such as TSLP. Thus, the airway epithelium and its cytokines may play a central role in controlling the immune network within the airway mucosa in asthma.