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United States Department of Agriculture

Agricultural Research Service

Research Project: DIET AND IMMUNE FUNCTION RELATED TO INFECTIOUS AND ALLERGIC DISEASE

Location: Diet, Genomics and Immunology Lab

Title: Role of macrophages in the altered epithelial function during a type 2 immune response induced by enteric nematode infection

Authors
item Notari, Luigi -
item Riera, D -
item Sun, Rex -
item Bohl, Jennifer -
item Mclean, L -
item Madden, Kathleen -
item Van Rooijen, Nico -
item Vanuytsel, Tim -
item Urban, Joseph
item Zhao, Aiping -
item Shea-Donohue, Terez -

Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 19, 2013
Publication Date: January 13, 2014
Repository URL: http://
Citation: Notari, L., Riera, D.C., Sun, R., Bohl, J.A., Mcclean, L.P., Madden, K., Vanrooijen, N., Vanuytsel, T., Urban Jr, J.F., Zhao, A., Shea-Donohue, T. 2014. Role of macrophages in the altered epithelial function during a type 2 immune response induced by enteric nematode infection. PLoS One. 23:9(1)e84763.

Interpretive Summary: Altered glucose metabolism is a feature of obesity that is often accompanied by inflammation. Parasitic nematode (worm) infections can induce a host immune response characterized by production of certain proteins called cytokines that can modulate inflammation and immune related affects on metabolism. Notably, worm infections have been shown to inhibit the spontaneous development of diabetes in non-obese diabetic mice and improve metabolic features of high fat diet-induced obesity including altered fat metabolism in the liver. Some of these effects appear to relate to parasite induced changes in an inflammatory cell in fat tissue called a macrophage that is partially responsible for improvements in obesity related inflammation. In the current study, we demonstrate that parasite infection also regulates glucose absorption in the intestine by mechanisms that are partially dependent on intestinal macrophage function. There appears to be a relationship between the activity of resident macrophages that have been functionally altered by the infection and glucose transporters on intestinal epithelial cells that control the absorption and release of glucose from the cell. This research will be useful to other scientists and clinicians who study and treat obesity and related metabolic disorders.

Technical Abstract: Two major functions of the intestinal epithelium are to act as a physical barrier and to regulate the movement of nutrients, ions and fluid. Nematode infection induces alterations in smooth and epithelial cell function, including increased fluid in the intestinal lumen, which are attributed to a STAT6-dependent increase in intestinal permeability and inhibition of sodium-linked glucose absorption. In the gut, glucose entry into epithelial cells occurs primarily through the unidirectional high affinity sodium-dependent glucose transporter-1 (SGLT-1), while exit from the basolateral aspect is through the facilitated transporter GLUT2. GLUT2 is also localized to the apical border when dietary glucose is high, while its presence on the cell surface is reduced by fasting. Parasitic enteric nematodes induce a type 2 immune response characterized by increased production of Th2 cytokines, IL-4 and IL-13, and recruitment of alternatively activated macrophages to the site of infection. There is an inverse correlation between the higher incidence of autoimmune diseases and the lower incidence of nematode infection in industrialized areas. Nematode infection also inhibited the spontaneous development of diabetes in non-obese diabetic mice and improves high fat diet-induced obesity. The current study was designed to investigate the mechanisms involved in nematode-induced alterations in epithelial cell function and glucose homeostasis. The results of our studies show that nematode infection alters intestinal glucose absorption by both macrophage-dependent and –independent mechanisms. We observed that the nematode-induced reductions in glucose absorption involved a macrophage-dependent inhibition of epithelial SGLT1 activity and leptin-mediated inhibition of GLUT2 resulting in a “lean” epithelial phenotype. These results provide a further link between metabolism and immune function that may contribute to the protective effect of infection from type-1 diabetes and obesity.

Last Modified: 8/1/2014
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