Allergic inflammation has crucial roles in allergic diseases such as asthma. It is therefore important to understand why and how the immune system responds to allergens. Here we found that full-length interleukin 33 (IL-33), an alarmin cytokine with critical roles in type 2 immunity and asthma, functioned as a protease sensor that detected proteolytic activities associated with various environmental allergens across four kingdoms, including fungi, house dust mites, bacteria and pollens. When exposed to allergen proteases, IL-33 was rapidly cleaved in its central 'sensor' domain, which led to activation of the production of type 2 cytokines in group 2 innate lymphoid cells. Preventing cleavage of IL-33 reduced allergic airway inflammation. Our findings reveal a molecular mechanism for the rapid induction of allergic type 2 inflammation following allergen exposure, with important implications for allergic diseases.
L’interleukine-33 est une cytokine nucléaire de la famille de l’IL-1, exprimée par les cellules endothéliales et épithéliales des tissus en contact avec l’environnement. Elle est libérée lors de dommages tissulaires et joue le rôle d’alarmine en prévenant le système immunitaire d’un danger. Elle est impliquée dans l’immunité innée de type-2 et l’inflammation allergique, mais des études récentes suggèrent qu’elle peut, selon le contexte environnemental, jouer d’autres rôles dans l’homéostasie ou l’immunité antivirale, par exemple. Elle est associée à de nombreuses pathologies, notamment allergiques, inflammatoires ou infectieuses, et pourrait être une cible thérapeutique de choix pour le traitement de l’asthme sévère.
Group 2 Innate Lymphoid Cells (ILC2) play an important role in immune responses at barrier surfaces, notably in the lung during airway allergic inflammation or asthma. Several studies have described methods to isolate ILC2s from wild-type naive mice, most of them using cell sorting to obtain a pure population. Here, we describe in detail, a simple, efficient method for isolation and culture of lung mouse ILC2s. Lungs from Rag2 -/mice pretreated with IL-33 are collected and processed into single cell suspensions. Lymphoid cells are then recovered by density gradient separation. Lin -CD45 + cells are selected by depletion of lineage positive cells followed by positive selection of CD45 + cells. Culture of the isolated cells for several days results in a highly purified ILC2 population expressing typical cell surface markers (CD90.2, Sca1, CD25, CD127, and IL-33R). These cells can be expanded in culture for up to 10 days and used for diverse ex vivo assays or in vivo adoptive transfer experiments.
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