Il-33 Facilitates Rapid Expulsion Of The Parasitic Nematode Strongyloides Ratti From The Intestine Via Ilc2-And Il-9-Driven Mast Cell Activation

Author summaryParasitic worms leave a trail of destruction while migrating through their host's tissue. Thereby they trigger the release of tissue-derived alarmin cytokines such as IL-33 that promote the initiation of efficient anti-helminth immune responses. Here we use mice infected with the parasitic nematode Strongyloides ratti to unravel the chain of events leading from parasite sensing to parasite expulsion. S. ratti penetrates the skin of its mammalian host, migrates via skin and muscle tissue to the mouth, is swallowed and reproduces in the small intestine. The parasite is eventually expelled from the intestine by the action of mast cells that are activated via IL-9. Using inhibitors and enhancers for IL-33 we demonstrate that the release of IL-33 during S. ratti infection activates mast cells. Blockade of IL-33 elevated intestinal parasite burden and suppressed mast cell degranulation while stabilization of endogenous IL-33 or application of recombinant IL-33 reduced intestinal parasite burdens and increased mast cell degranulation. IL-33 mediated parasite expulsion independently of adaptive immunity, basophils or granulocytes but dependent on IL-9, innate lymphoid cells and mast cells. In summary we provide an example of how efficient sensing of a tissue-migrating parasite generates a hostile environment in the intestine that facilitates parasite expulsion.Parasitic helminths are sensed by the immune system via tissue-derived alarmins that promote the initiation of the appropriate type 2 immune responses. Here we establish the nuclear alarmin cytokine IL-33 as a non-redundant trigger of specifically IL-9-driven and mast cell-mediated immunity to the intestinal parasite Strongyloides ratti. Blockade of endogenous IL-33 using a helminth-derived IL-33 inhibitor elevated intestinal parasite burdens in the context of reduced mast cell activation while stabilization of endogenous IL-33 or application of recombinant IL-33 reciprocally reduced intestinal parasite burdens and increased mast cell activation. Using gene-deficient mice, we show that application of IL-33 triggered rapid mast cell-mediated expulsion of parasites directly in the intestine, independent of the adaptive immune system, basophils, eosinophils or Gr-1(+) cells but dependent on functional IL-9 receptor and innate lymphoid cells (ILC). Thereby we connect the described axis of IL-33-mediated ILC2 expansion to the rapid initiation of IL-9-mediated and mast cell-driven intestinal anti-helminth immunity.