Interleukin-13 Receptor Alpha 1-Dependent Responses In The Intestine Are Critical To Parasite Clearance

Nematode infection upregulates interleukin-4 (IL-4) and IL-13 and induces STAT6-dependent changes in gut function that promote worm clearance. IL-4 and IL-13 activate the type 2 IL-4 receptor (IL-4R), which contains the IL-13R alpha 1 and IL-4R alpha chains. We used mice deficient in IL-13R alpha 1 (IL-13R alpha 1(-/-)) to examine the contribution of IL-13 acting at the type 2 IL-4R to immune and functional responses to primary (Hb1) and secondary (Hb2) infections with the gastrointestinal nematode parasite Heligmosomoides bakeri. There were differences between strains in the IL-4 and IL-13 expression responses to Hb1 but not Hb2 infection. Following Hb2 infection, deficient mice had impaired worm expulsion and higher worm fecundity despite normal production of Th2-derived cytokines. The upregulation of IL-25 and IL-13R alpha 2 in Hb1- and Hb2-infected wild-type (WT) mice was absent in IL-13R alpha 1(-/-) mice. Goblet cell numbers and resistin-like molecule beta (RELM-beta) expression were attenuated significantly in IL-13R alpha 1(-/-) mice following Hb2 infections. IL-13R alpha 1 contributes to the development of alternatively activated macrophages, but the type 1 IL-4R is also important. Hb1 infection had no effects on smooth muscle function or epithelial permeability in either strain, while the enhanced mucosal permeability and changes in smooth muscle function and morphology observed in response to Hb2 infection in WT mice were absent in IL-13R alpha 1(-/-) mice. Notably, the contribution of claudin-2, which has been linked to IL-13, does not mediate the increased mucosal permeability following Hb2 infection. These results show that activation of IL-13R alpha 1 is critical for key aspects of the immune and functional responses to Hb2 infection that facilitate expulsion.