Resistance to a Helminthic Infection is Dependent on Mast Cell Activation Mediated by ATP in Spi-B-deficient Mice

We have evaluated protective roles for mast cells against infection with an intestinal nematode, Heligmosomoides polygyrus (Hp) utilizing a mutant mouse strain that genetically lacks the Spi-B transcriptional factor (Spi-BKO). These mice exhibiting the increase in mast cells very quickly expelled the worms in association with induction of group 2 innate lymphoid cells (ILC2) producing IL-13 and goblet cell hyperplasia in the intestinal epithelium. Mast cells were rapidly activated in response to ATP, released from apoptotic intestinal epithelial cells immediately after Hp infection, followed by production of IL-33 and IL-25. In vivo inhibition of ATP with P₂X₇ receptor on mast cells using a selective inhibitor abolished mast cell activation and induction of IL-13-producing ILC2, which rendered Spi-BKO mice susceptible to Hp. These results clearly demonstrate that activation of mast cells by ATP orchestrates the development of protective type 2 responses by producing IL-33 and IL-25 both of which are crucial for ILC2 activation.