IL-13 working through IL-13Ra1 mediates critical functional responses to nematode infection in the gastrointestinal tract

Authors: SUN, REX - University Of Maryland; NOTARI, LUIGI - University Of Maryland; VANUYTSEL, TIM - University Of Leuven; MADDEN, KATHLEEN - Uniform Services Medical Center; BOHL, JENNIFER - University Of Maryland; RAMALINGAM, THIRUMALAI - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH); WYNN, THOMAS - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH); Urban, Joseph; ZHAO, AIPING - University Of Maryland; SHEA-DONOHUE, TEREZ - University Of Maryland

Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/24/2016
Publication Date: 4/1/2016
Citation: Sun, R., Notari, L., Vanuytsel, T., Madden, K., Bohl, J., Ramalingam, T.R., Wynn, T.A., Urban Jr, J.F., Zhao, A., Shea-Donohue, T. 2016. Interleukin-13 receptor a1-dependent responses in the intestine are critical to parasite clearance. Infection and Immunity. 84(4):1032-1044. doi: 10.1128IAI.00990-009915.

Interpretive Summary: Parasite nematode (worm) infections induce an allergy related immune response characterized by production of certain proteins called cytokines that regulate inflammatory diseases. A component of this response alters intestinal smooth muscle and epithelial cell function. This includes changes in the absorption of glucose. Here we investigated how the absence of a primary receptor for the cytokine IL-13 can interfere with normal intestinal function and block protective immunity to a worm infection. We also observed that IL-13-induced changes in epithelial cell permeability could be distinguished from alterations in gap junctions between epithelial cells. The functional dissociation of intestinal permeability is important in the context of clinical and experimental colitis, and the absorption of nutrients. This research will be useful to other scientists and clinicians who study and treat allergy, parasitic diseases, and related metabolic disorders.

Technical Abstract: Nematode infection up-regulates IL-4 and IL-13 and induces STAT6-dependent changes in epithelial function and smooth muscle contractility that promote worm clearance. IL-4 and IL-13 share the same type II IL-4R that contains the IL-13R'1 and the IL-4R' chain linked to STAT6. The role of IL-13 working through IL-13Ra1 in nematode infection-induced changes in the intestine was investigated. Mice deficient in IL-13Ra1 (IL-13Ra1-/-) were used to examine the contribution of IL-13 to immune and functional responses to infection with Heligmosomoides bakeri(Hb). Gene expression of cytokines, macrophage markers, and tight junction proteins were assessed by PCR and protein expression by Western blot. Intestinal smooth muscle contractility and intestinal mucosa ion secretion and glucose absorption were evaluated. IL-13Ra1-/- mice had impaired adult worm expulsion despite normal production of Th2 cytokines. Goblet cell numbers and Relmß production were significantly attenuated following infection of IL-13Ra1-/- mice. Alternatively activated macrophage marker expression was attenuated significantly in secondary but not primary Hb infection of IL-13Ra1-/- mice. Smooth muscle hyper-contractility and hypertrophy, and enhanced permeability observed in Hb-infected wild-type mice was absent in Hb-infected IL-13Ra1-/- mice despite significant up-regulation of mMCP1 and claudin-2. Glucose absorption was attenuated in Hb-infected IL-13Ra1-/- mice. Hb-induced alterations in smooth muscle morphology and function were mediated directly by IL-13 and/or indirectly through production of growth factors like IGF-1, and Hb-induced changes in mucosal permeability were independent of mast cells and claudin-2. The dissociation between IL-13 and claudin-2-induced permeability is important in the context of clinical and experimental colitis.