Mast Cells Are Crucial for Induction of Group 2 Innate Lymphoid Cells and Clearance of Helminth Infections

Abstract

Mast cells are important for eradication of intestinal nematodes; however, their precise mechanisms of action have remained elusive, especially in the early phase of infection. We found that Spi-B-deficient mice had increased numbers of mast cells and rapidly expelled the Heligmosomoides polygyrus (Hp) nematode. This was accompanied by induction of interleukin-13 (IL-13)-producing group 2 innate lymphoid cells (ILC2) and goblet cell hyperplasia. Immediately after Hp infection, mast cells were rapidly activated to produce IL-33 in response to ATP released from apoptotic intestinal epithelial cells. In vivo inhibition of the P2X7 ATP receptor rendered the Spi-B-deficient mice susceptible to Hp, concomitant with elimination of mast cell activation and IL-13-producing ILC2 induction. These results uncover a previously unknown role for mast cells in innate immunity in that activation of mast cells by ATP orchestrates the development of a protective type 2 immune response, in part by producing IL-33, which contributes to ILC2 activation.

Immunity to gastrointestinal nematode infections

“…43,44 It belongs to the IL-1 family of cytokines and is thus translated in a proform that can be further processed. However, in contrast to IL-1b and IL-18, IL-33 is biologically active before cleavage and can localize to the nucleus where it binds chromatin, which is augmented upon T. spiralis infection.…”

“…Interestingly, a recent study also found that mast cells not only can respond to IL-33 but might also enhance the transmission of type 2 signals by the production of IL-33 in response to adenosine triphosphate release by dying epithelial cells. 44 …”

Type 2 Cytokine Responses: Regulating Immunity to Helminth Parasites and Allergic Inflammation

“…To date, the contributions of ILC2s to host-protective responses in the context of other helminths are less defined. A recent study by Shimokawa et al has shown that mast cells cooperate with ILC2s to promote immunity to H. polygyrus (53). Specifically, they reported that ATP-activated mast cells promote ILC2 responses via their secretion of IL-33 and that these events contribute to reduced parasite burdens (53).…”

“…A recent study by Shimokawa et al has shown that mast cells cooperate with ILC2s to promote immunity to H. polygyrus (53). Specifically, they reported that ATP-activated mast cells promote ILC2 responses via their secretion of IL-33 and that these events contribute to reduced parasite burdens (53). Additional studies report that ILC2s promote the differentiation of T H 2 cells following H. polygyrus infection via their secretion of IL-4(54), and preliminary reports suggest that ILC2s may contribute to host-protective responses against Strongyloides venezuelensis , T. muris and Schistosoma species(55–57).…”

“…Recent work has also shown that Spi-B-deficient mice, which have increased numbers of mast cells, exhibit significantly improved immunity to H. polygyrus . Specifically, mast cell-derived IL-33 stimulated was shown to promote IL-13-producing ILC2s that lead to goblet cell hyperplasia and rapid worm expulsion in Spi-B-deficient mice (53). In addition to promoting anti-helminth immunity, mast cells are well recognized for their contributions to allergic disease states as is compressively highlighted in the following review articles(132, 133).…”