|VAN ROOIJEN, NICO|
Submitted to: Gastroenterology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/4/2008
Publication Date: 7/1/2008
Citation: Zhao, A., Urban Jr, J.F., Anthony, R.M., Sun, R., Stiltz, J., van Rooijen, N., Wynn, T.A., Gause, W.C., Shea-Donohue, T. 2008. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages. Gastroenterology. 135(1):217-225.
Interpretive Summary: Parasitic worm infection in the intestine acts like food allergens because of the nature of the immune response that is induced, including the release of the immune mediators IL-4 and IL-13. These mediators are also induced during allergic disease and regulate a number of immune and non-immune functions. Food particles and worms change the nature of cells that migrate to the intestine, and these cells, in turn, regulate both immune function and intestinal physiology. We observed that worm infection induced local macrophage cells to develop in the intestine and metabolize the essential amino arginine to products that control tissue remodeling and control smooth muscle function. The location and metabolism of these cells not only controls how muscle contractility contributes to protection against allergens, but how the tissue returns to normal once the provocation has been cleared from the gut. This work will be of interest to nutritionists who study food allergy, clinicians that evaluate intestinal function, and scientists interested in the role of parasitic infection in host immunity and nutrient absorption.
Technical Abstract: Enteric nematode infection induces a strong Th2 cytokine response and is characterized by increased infiltration of various immune cells including macrophages. The role of these immune cells in host defense against enteric nematode infection, however, remains poorly defined. The present study investigated the role of macrophages and the arginase pathway in nematode-induced changes in intestinal smooth muscle function and worm expulsion. Mice were infected with Nippostrongylus brasiliensis, and were iv injected with clodronateliposome to deplete macrophages or given BEC in drinking water to inhibit arginase activities. The phenotype of macrophages was monitored by measuring the mRNA expressions of the specific molecular markers via real-time PCR or by immunofluoresence staining. Nippostrongylus brasiliensis infection caused an increased infiltration of macrophages, characterized by the up regulation of specific markers for alternatively activated macrophages that was dependent on IL-4 or IL-13 activation of STAT6. Elimination of alternatively activated macrophages by treating mice with clodronateliposome blocked smooth muscle hyper-contractility and hypertrophy, and prevented worm expulsion. Specific inhibition of arginase activity interfered with smooth muscle contractility, but only partially affected protective immunity. These data show that alternatively activated macrophages constitute a major effector of the downstream events of Th2 cytokines IL-4/IL-13 effects on intestinal smooth muscle function. This suggests that the intestinal smooth muscle is responsive to signals generated by resident and infiltrating macrophages that change functional expression based on local immune cytokine stimulation.