Defining the role of IL-18 in atopic dermatitis
NIH
WASHINGTON UNIVERSITY
ABSTRACT Atopic dermatitis (AD) is an increasingly common relapsing-remitting skin disease characterized by chronic allergic inflammation and itch. The etiology of AD is unknown, but type 2 cytokines, particularly interleukin (IL)- 4 and IL-13, are involved in driving AD and AD-like pathology, as demonstrated by the efficacy of therapies targeting these cytokines in human AD. Among type 2 cytokine producers, basophils and group 2 innate lymphoid cells (ILC2s) are dysregulated in human AD and are major sources of type 2 cytokines in mouse models of allergic inflammation, yet how these cells are triggered in AD and AD-like disease remain unresolved. Our recent single-cell RNA sequencing (scRNAseq) analysis identified high expression of IL-18 receptor (IL-18R, Il18r1) among skin ILC2s in comparison to ILC2s isolated from other tissues, and we further observed robust production of type 2 cytokines from IL-18-stimulated skin ILC2s, indicating that IL-18 is a candidate driver of type 2 cytokine production in AD-associated allergic skin inflammation. Basophils are also potently activated by IL-18 to produce type 2 cytokines, and our studies have demonstrated that basophils mediate acute itch flares in the context of AD-like disease, suggesting that IL-18 may mediate aspects of AD- related itch. Additionally, we find that IL-18 is elevated in both the skin and plasma of patients with moderate- to-severe AD, and that ILC2s and basophils exhibit unique activation profiles in human AD. Together, these data suggest that IL-18 mediates ILC2 and basophil functions to influence itch and AD pathogenesis. Thus, we hypothesize that IL-18 is a key regulator and potential therapeutic target in AD. In this project, we will determine how IL-18 influences basophil and ILC2 effector functions in the context of AD-associated inflammation and itch behavior. To do this, we will test several novel mouse strains in models of AD-like skin inflammation and translate these findings to human AD settings using innovative spatial transcriptomics approaches. We plan to test our hypothesis and accomplish our overall objective by pursuing three specific aims: 1. Test the contribution of IL-18 to skin ILC2 responses and AD-like disease. 2. Determine whether IL-18 activates basophils to trigger acute itch flares. 3. Examine the relationships between IL-18, ILC2s, and basophils in human AD by spatial transcriptomics. Understanding of how IL-18 contributes to the initiation and propagation of AD in mouse models and in human disease may advance new therapeutic approaches designed to ameliorate inflammation and itch in AD. PROJECT NARRATIVE Atopic dermatitis (AD) is a chronic skin disease marked by allergic inflammation and itch, and is increasingly common among children and adults in the United States. We and others have found that the cytokine IL-18 is dysregulated in human AD, along with IL-18-responsive basophils and group 2 innate lymphoid cells (ILC2s). In this proposal, we investigate the role of IL-18 in mediating ILC2 and basophil responses in AD and AD-like skin disease, in order to advance our mechanistic understanding of AD pathogenesis.
Non-SBIR/STTR