IL-33 priming amplifies ATP-mediated mast cell cytokine production

Inflammatory responses are required to block pathogen infection but can also lead to hypersensitivity and chronic inflammation. Barrier tissues actively release IL-33, ATP, and other alarmins during cell stress, helping identify pathogenic stimuli. However, it is unclear how these signals are integrated. Mast cells are critical initiators of allergic inflammation and respond to IL-33 and ATP. We found that mouse mast cells had a 3-6-fold increase in ATP-induced cytokine production when pre-treated with IL-33. This effect was observed at ATP concentrations < 100 mu M and required < 30-minute IL-33 exposure. ATP-induced degranulation was not enhanced by pretreatment nor was the response to several pathogen molecules. Mechanistic studies implicated the P2X7 receptor and calcineurin/NFAT pathway in the enhanced ATP response. Finally, we found that IL-33 + ATP co-stimulation enhanced peritoneal eosinophil and macrophage recruitment. These results support the hypothesis that alarmins collaborate to surpass a threshold necessary to initiate an inflammatory response.

Automated summary

Inflammatory responses are necessary for blocking pathogen infection but can also lead to hypersensitivity and chronic inflammation. This study found that IL-33 enhances the ATP-induced cytokine production in mast cells, potentially through the P2X7 receptor and calcineurin/NFAT pathway. Furthermore, IL-33 + ATP co-stimulation enhances the recruitment of eosinophils and macrophages.