Location: Diet, Genomics and Immunology LaboratoryTitle: SerpinB2 is critical to Th2 immunity against enteric nematode infection Author
Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/29/2013
Publication Date: 6/1/2013
Citation: Zhao, A., Yang, Z., Sun, R., Grinchuk, V., Netzel-Arnett, S., Anglin, I.E., Driesbaugh, K.H., Notari, L., Bohl, J.A., Madden, K.B., Urban Jr, J.F., Antalis, T.M., Shea-Donahue 2013. SerpinB2 is critical to Th2 immunity against enteric nematode infection. Journal of Immunology. 190(11):5779-87. Interpretive Summary: The primary function of the intestine as a site of nutrient absorption can be perturbed by infection as the resulting immune and inflammatory responses alter the function of intestinal epithelial and smooth muscle cells. The current study showed that the absence of a member of the serine protease inhibitor family, SerpinB, in macrophages resulted in a defect in expulsion of a parasite worm from the intestine that was due to reduced trafficking and development of macrophages in the intestinal tissues. This caused a significant reduction in parasite-induced intestinal smooth muscle hyper-contractility and a delayed increase mucosal permeability. This work showed how events that activate the intestinal immune system such as food allergens and parasitic infection can influence intestinal physiological function. The information is important to researchers that study the control of infectious diseases in humans and livestock, and the relationship between parasitic infection, allergic disease, and intestinal responses that affect nutrition and health.
Technical Abstract: SerpinB2, a member of the serine protease inhibitor family, is expressed by macrophages and up-regulated significantly by inflammation. Recent studies implicated a role for SerpinB2 in the control of Th1 and Th2 immune responses, but the mechanisms of these effects are unknown. In the current study, we used mice deficient (-/-) in SerpinB2 to investigate its role in the host response to the enteric nematode, Heligmosomoides bakeri (Hb). Nematode infection induced a STAT6-dependent increase in SerpinB2 expression. The Hb-induced up-regulation of IL-4 and IL-13 gene expression was attenuated in SerpinB2(-/-) mice coincident with a decrease in IL-13 protein and impaired worm clearance. The impaired Th2 responses were associated with a loss of the Hb-induced smooth muscle hyper-contractility and a significant delay in infection-induced increase in mucosal permeability. Th2 responses are linked to CCL2-mediated increase in the infiltration of macrophages that become alternatively activated (M2). In SerpinB2(-/-) mice, there was an impaired infiltration of macrophages, and a decrease in CCL2 and M2 marker expression. Studies in macrophages isolated from SerpinB2(-/-) mice showed a reduced CCL2 expression but normal M2 marker expression in response to Th2 cytokines. These data demonstrate that the immune regulation of SerpinB2 expression plays a critical role in the development of Th2-mediated protective immunity against nematode infection by a mechanism involving CCL2 production and macrophage infiltration.