Background: Interleukin (IL) 33 is a pleiotropic cytokine involved in numerous diseases including asthma and induces a novel subtype of innate cells called nuocytes. The signalling pathway of IL-33 resembles other IL-1 cytokines, but the role of the serine-threonine kinase mammalian target of rapamycin (mTOR) in IL-33 function in vitro and in vivo is unknown. Rapamycin is a specific mTOR inhibitor that acts as an immunosuppressant. Methods: Model 1: BALB/c mice were treated with IL-33 intranasally for five consecutive days +rapamycin. Model 2: wild-type nuocytes were transferred into IL-33 receptor knockout (ST2-/-) mice and treated with IL-33 + rapamycin for five days. On day 6 bronchoalveolar lavage (BAL) and lungs were assayed for cell infiltration and cytokine levels. Ex vivo wild-type nuocytes were sorted using fluorescence activated cell sorting and treated in vitro with IL-33+rapamycin. Results: Intranasal IL-33 induces airway inflammation and nuocytes in the lung that produce type-2 cytokines (IL-5 and IL-13), which are inhibited by rapamycin. Ex vivo nuocytes treated with IL-33 produce type-2 cytokines in an mTOR-dependent manner. Adoptive transfers of wild-type nuocytes were sufficient to restore IL-33-driven airway inflammation in ST2-/mice in an mTOR-dependent manner. Conclusion: IL-33-induced airway inflammation and cytokine production is inhibited by rapamycin. Nuocytes produce type-2 cytokines in response to IL-33 in an mTOR-dependent manner. Nuocytes are sufficient to drive IL-33-induced, mTOR-dependent airway inflammation.
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