Submitted to: Journal of Immunology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 6/1/2009
Publication Date: 7/8/2009
Citation: Morimoto, M., Zhao, A., Sun, R., Stiltz, J., Madden, K.B., Mentink-Kane, M., Ramalingam, T., Wynn, T.A., Urban Jr, J.F., Shea-Donohue, T. 2009. IL-13 receptor alpha-2 regulates the immune and functional response to Nippostrongylus brasiliensis infection. Journal of Immunology. 183(3):1934-1999. Interpretive Summary: Parasitic worm infections are convenient models to examine allergic responses in the intestine that represent responses to food allergens because of the nature of the immune response that is induced in the intestine, including the release of the immune factors---cytokines like IL-4 and IL-13. These cytokine mediators are also induced during allergic disease and regulate a number of immune and non-immune functions. Both food particles and worms change the nature of cells that migrate to the intestine in response to their presence and these cells, in turn, regulate both immune function and intestinal physiology. We observed that in the absence of a key decoy receptor for the cytokine IL-13, there is a marked change in both intestinal smooth muscle and epithelial cell function during a worm infection. There is also a considerable increase in lumen fluid and decreased glucose absorption in the gut. These data indicate that the decoy receptor helps to control some of the negative effects of IL-13 on local nutrient uptake and metabolism in the intestine during parasite infection and allergic responses to foods. This work will be of interest to nutritionists who study food allergy, clinicians that evaluate intestinal function, and scientists interested in the regulation of harmful side effects of parasitic infection and allergic disease on host immunity and nutrient absorption.
Technical Abstract: IL-13 has a prominent role in host defense against the gastrointestinal nematode, Nippostrongylus brasiliensis; however, the role of IL-13 alpha2 in the immune and functional response to enteric infection is not known. In the current study, we investigated changes in smooth muscle and epithelial cell function, as well as alterations in gene expression of IL-13 and IL-4 and their receptors using laser capture micro dissection of specific cell types in the small intestine of N. brasiliensis-infected mice. An infection-induced up-regulation of IL-13Ralpha2 gene expression was confined to smooth muscle and was dependent on STAT6 and IL-13, but not on IL-4. In contrast, expression of IL-13Ralpha1 was reduced, indicating that changes in IL-13alpha2 expression serve to limit the biological effects of IL-13. The increased availability of IL-13 in IL-13Ralpha2-/- mice resulted in marked changes in constitutive epithelial and smooth muscle function. In addition, maximal changes in smooth muscle hyper contractility and epithelial cell resistance peaked earlier after infection in IL-13Ralpha2-/- compared to wild-type (WT) mice. This did not coincide with an earlier Th2 immune response as expression of IL-4 and IL-13 was attenuated in IL-13Ralpha2 mice, and worm expulsion was similar to WT mice. These data show that IL-13Ralpha2 plays an important role in nematode infection by limiting the availability of IL-13 during infection thereby regulating both the immune and biological effects of IL-13.