Stat6 Signaling Promotes Protective Immunity Against Trichinella spiralis Through a Mast Cell- and T Cell-Dependent Mechanism

Abstract

Studies in mice infected with the gastrointestinal nematode parasite Nippostrongylus brasiliensis demonstrated that IL-4/IL-13 activation of Stat6 suppresses development of intestinal mastocytosis and does not contribute to IL-4/IL-13 production, but is still essential for parasite expulsion. Because expulsion of another gastrointestinal nematode, Trichinella spiralis, unlike N. brasiliensis expulsion, is mast cell dependent, these observations suggested that T. spiralis expulsion would be Stat6 independent. Instead, we find that Stat6 activation by IL-4/IL-13 is required in T. spiralis-infected mice for the mast cell responses that induce worm expulsion and for the cytokine responses that induce intestinal mastocytosis. Furthermore, although IL-4 induces N. brasiliensis expulsion in the absence of B cells, T cells, and mast cells, mast cells and T cells are required for IL-4 induction of T. spiralis expulsion. Thus, Stat6 signaling is required for host protection against N. brasiliensis and T. spiralis but contributes to expulsion of these two worms by different mechanisms. The induction of multiple effector mechanisms by Stat6 signaling provides a way for a cytokine response induced by most gastrointestinal nematode parasites to protect against most of these parasites, even though different effector mechanisms are required for protection against different nematodes.

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

“…We have shown that IL-13 (and IL-4R␣), but not IL-4, is required for T. spiralis expulsion. Urban et al (20) found that worm expulsion was enhanced when mice were treated with exogenous IL-4, but, like us, found that mice deficient for IL-4 expel their worm burden at the same rate as wild-type mice. They also showed that IL-4-deficient mice failed to expel if treated with sIL-13R␣2, thus indicating that both IL-13 and IL-4 are important in resistance to this nematode.…”

“…These different findings may be attributable, at least in part, to the different mouse strains used in these studies. STAT-6 is required for both IL-4 and IL-13 signaling, and is essential for the expulsion of both T. spiralis and N. brasiliensis from the intestine (20,21). We have shown that IL-13 (and IL-4R␣), but not IL-4, is required for T. spiralis expulsion.…”

“…T cells are required for worm expulsion from the gut, but this is not IL-4 dependent, because mice genetically deficient for IL-4 can expel normally (19). However, expulsion is inhibited in mice deficient in the IL-4/IL-13 signaling molecules IL-4R␣ or STAT6, suggesting a role for IL-13 (19,20). IL-13 is certainly critical for expulsion of another gastrointestinal nematode, Nippostrongylus brasiliensis, which inhabits the lumen of the small intestine (21), and resolution of Trichuris muris infection of the large bowel is also dependent on IL-13 via the production of TNF-␣ (22).…”

Role of STAT6 and Mast Cells in IL-4- and IL-13-Induced Alterations in Murine Intestinal Epithelial Cell Function

“…I sc responses to PGE 2 and histamine were significantly enhanced only in the IL-4C-treated ϩ/ϩ mice, suggesting that these prosecretory effects of IL-4 are mast cell dependent. Because IL-4 induction of intestinal mastocytosis and mast cell degranulation are STAT6 independent (22,23) (Fig. 3), we expected that the mast cell-dependent mechanism by which IL-4 increases the response to histamine and PGE 2 would also be STAT6 independent.…”

Eosinophils and Trichinella infection: toxic for the parasite and the host?

“…Studies using IL-4 or IL-4-receptor-α deficient mice revealed that IL-4 has a crucial role in worm expulsion [43,44]. However, it is not clear whether IL-5 and/or eosinophils can be implicated in the protective response of the host against the parasite.…”