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Title: Recirculating immunocompetent cells in colitic mice intensify their lung response to bacterial endotoxin

item METWALI, AHMED - University Of Iowa
item THORNE, PETER - University Of Iowa
item INCE, M - University Of Iowa
item METWALI, NERVANA - University Of Iowa
item WINCKLER, SARAH - University Of Iowa
item GUAN, XIAOQUN - University Of Iowa
item BEYATLI, SONAY - University Of Iowa
item TRUSCOTT, JAMIE - University Of Iowa
item Urban, Joseph
item ELLIOTT, DAVID - University Of Iowa

Submitted to: Digestive Disease and Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/11/2018
Publication Date: 11/1/2018
Citation: Metwali, A., Thorne, P.S., Ince, M.N., Metwali, N., Winckler, S., Guan, X., Beyatli, S., Truscott, J., Urban Jr, J.F., Elliott, D.E. 2018. Recirculating immunocompetent cells in colitic mice intensify their lung response to bacterial endotoxin. Digestive Disease and Science. 63(11)2930-2939.

Interpretive Summary: Helminths (parasitic worms) are complex organisms that alter host immune responses and suppress pro-inflammatory responses that can reduce pathology in animal models of inflammation. Modern loss of previously ubiquitous worm exposure in humans likely has contributed to the recent rise of immune-mediated diseases in modern societies. Heligmosomoides polygyrus bakeri (Hpb) is a parasitic worm that infects mice and resides in the intestine. Inoculation of mice with Hpb can reverse expression of colitis by enhancing the activity of regulatory T cells that, in turn, suppress gut-associated pro-inflammatory cell function. The current work shows that protein messenger molecules secreted by regulatory cells are responsible for directing these regulatory circuits in the intestine. These secreted proteins act through cell surface receptors to activate an intracellular molecule called Stat6 which is important in the function of the cells. Blocking these secreted molecules short circuits the signaling pathway and blocks expulsion of the worm from the intestine, but it also reduces the role of the worm infection in reducing inflammation associated with colitis. This work indicates that there is an important balance in the expression of immune and inflammatory pathways that requires careful tuning in order to facilitate the appropriate type of response that is both protective against pathogens without exacerbating inflammation. This work is important to clinicians that require tools to regulate immunity and inflammation, and indicates a role of diet and nutrition in the ultimate expression of a response that is appropriate to intestinal health.

Technical Abstract: Infection with helminths alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6- signaling. We examined the importance of intact T cell Stat6-signaling on helminth-induced suppression of murine colitis activated by T cell transfer. Mice infected with the intestinal nematode Heligmosomoides polygyrus bakeri resolved established wildtype T cell transfer-induced colitis. However, if the transferred T cells lack intact Stat6, then helminth infection failed to attenuate colitis or suppress MLN T cell IFN or IL17 production. Loss of regulation was associated with strong induction of the IFN+Foxp3+ MLN T cell compartment. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that was also not attenuated by helminth infection. These results show that T cell expression of responsive Stat6 signaling is required for regulation of pathogenic inflammation induced by helminth infection.