Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri

Abstract

f Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb, were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri. Genetic deletion of IL-25 (IL-25 ؊/؊ ) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25 ؊/؊ mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25 ؊/؊ mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.A lthough studies using mouse models have advanced our understanding of the molecular and cellular mechanisms underlying host protection against nematode infection, many of the details remain to be fully elucidated. Infection with gastrointestinal nematode parasites induces a polarized Th2 immune response featuring elevated levels of production of interleukin-4 (IL-4), IL-5, and IL-13. IL-4 and IL-13 activate STAT6 signaling pathways, leading to characteristic alterations in intestinal function that facilitate worm expulsion. IL-25, also called IL-17E, is a cytokine member of the IL-17 family that includes IL-17A through IL-17F. Unlike other members of the IL-17 family that are involved in various inflammatory pathologies, IL-25 possesses immune-modulating properties that inhibit Th1/Th17-associated inflammation.It has been observed that intestinal epithelium-derived IL-25 plays a pivotal role in the initiation of the host protective immune cascade against nematode infection. In particular, intestinal epithelial tuft cells produce IL-25 (1, 2) in response to early-stage worm infection, leading to the expansion and activation of type 2 innate lymphoid cells (ILC2), a recently identified noncytotoxic innate lymphoid cell (ILC) family member that has a classic lymphoid cell morphology but that lacks the expression of cell surface markers of other known immune lymphocytes (3, 4). The activated ILC2 then release Th2-associated cytokines IL-5 a...

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