Targeting the Epithelium-Derived Innate Cytokines: From Bench to Bedside

Abstract

When epithelial cells are exposed to potentially threatening external stimuli such as allergens, bacteria, viruses, and helminths, they instantly produce "alarmin" cytokines, namely, IL-33, IL-25, and TSLP. These alarmins alert the immune system about these threats, thereby mobilizing host immune defense mechanisms. Specifically, the alarmins strongly stimulate type-2 immune cells, including eosinophils, mast cells, dendritic cells, type-2 helper T cells, and type-2 innate lymphoid cells. Given that the alarm-raising role of IL-33, IL-25, and TSLP was first detected in allergic and infectious diseases, most studies on alarmins focus on their role in these diseases. However, recent studies suggest that alarmins also have a broad range of effector functions in other pathological conditions, including psoriasis, multiple sclerosis, and cancer. Therefore, this review provides an update on the epithelium-derived cytokines in both allergic and non-allergic diseases. We also review the progress of clinical trials on biological agents that target the alarmins and discuss the therapeutic potential of these agents in non-allergic diseases.

Keywords: Alarmins; Autoimmune disease; Biological therapy; Hypersensitivity.

Figure 1. Cellular targets of IL-25, IL-33, and TSLP in allergic diseases. Genetic defects and environmental stimuli stimulate epithelial cells to secret alarmins. These cytokines exert pro-inflammatory effects by acting on a wide range of cell populations. Specifically, they can 1) enhance the survival, recruitment, and degranulation of granulocytes such as eosinophils and mast cells; 2) immediately cause ILC2s to secrete IL-5 and IL-13; 3) act directly on T_H2 cells since they induce their terminal differentiation in peripheral inflamed tissues; 4) convert ST2-expressing Tregs into T_H2-like Tregs that produce IL-5 and IL-13; and 5) act on somatosensory neurons and keratinocytes, thereby promoting itching and disrupting the skin barrier, respectively.

Figure 2. The receptors and downstream signaling of each alarmin. IL-33 binds to a heterodimeric receptor composed of ST2 and IL-1RAP. Ligation of IL-33 recruits and activates the adaptor protein MyD88. MyD88 activates the transcription factors NF-κB and AP-1, which are then delivered to the nucleus and bind to specific DNA motifs. IL-25 exerts its pro-inflammatory effects by binding to a heterodimeric receptor composed of IL-17RA and IL-17RB. The intracellular domain of the IL-25 receptor recruits ACT1 and TRAF6 and subsequently promotes the activation of the NF-κB or ERK-JNK signaling axis. TSLP binds to TSLPR paired with IL-7Rα. This ligation event activates TSLP receptor-associated JAK1 and JAK2, which activate the transcription factor STAT5, thereby causing it to translocate into the nucleus. All of these alarmin signaling pathways lead to the production of type-2 cytokines and chemokines by the target cells.

IL-1RAP, IL-1 receptor accessory protein.