Abstract
Interleukin-33 (IL-33) is an IL-1 family cytokine that signals via its receptor T1/ST2, and is a key regulator of inflammation, notably the type-2 response implicated in allergic asthma. Critical to our understanding of the role of IL-33 is the identification of the cellular sources of IL-33. Although progress has been made in this area, the development of a robust live cell reporter of expression would allow the localisation of IL-33 during ongoing immune responses. We have generated a fluorescent reporter mouse line, Il33Cit/+, to define the expression profile of IL-33 in vivo and demonstrate its temporal and spatial expression during experimental allergic asthma responses. We found that type-2 pneumocytes constitute the major source of IL-33 upon allergic lung inflammation following exposure to OVA, fungal extract or ragweed pollen. Using Il33Cit/Cit mice (IL-33-deficient), we establish a role for IL-33 early in the initiation of type-2 responses and the induction of nuocytes (ILC2). We also demonstrate a potential mechanism of action by which IL-33 rapidly initiates type-2 immune responses. Il33Cit/+ mice have enabled new insights into the initiation of type-2 responses and will provide an important tool for further dissection of this important inflammatory pathway in vivo.
Highlights
Type-2 immune responses are characterised by the production of the cytokines IL-4, IL-5 [1], IL-9 [2] and IL-13 [3] and constitute the host’s defence against helminthic worm infections
Allergic asthma results from inappropriate activation of the type-2 immune responses in the lung triggered by contact with innocuous allergens, such as pollen
This report defines in vivo cellular sources of IL-33 in both naıve mice and mice undergoing allergic lung responses
Summary
Type-2 immune responses are characterised by the production of the cytokines IL-4, IL-5 [1], IL-9 [2] and IL-13 [3] and constitute the host’s defence against helminthic worm infections. Allergic asthma results from inappropriate activation of the type-2 immune responses in the lung triggered by contact with innocuous allergens, such as pollen. The type-2 response leads to the respiratory distress characteristic of asthma [6]. IL-33 binds to the receptor T1/ST2 via its C terminal region and thereby initiates a type-2 immune response [10]. In activating this response, IL-33 shares a level of redundancy with IL-25, the exact nature of this functional overlap is not well understood. T1/ST2 is present on subsets of Th2 cells which, when activated, produce type-2 cytokines [1]. Nuocytes [14,15,16,17,18], basophils [19], mast cells and eosinophils express the
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