Nematode Infection Induces Intestinal Pathology Associated With

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Nematode Infection Induces Intestinal Pathology Associated With Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection This information is current as Jacqueline R. McDermott, Neil E. Humphreys, Simon P. of September 29, 2021. Forman, Debra D. Donaldson and Richard K. Grencis J Immunol 2005; 175:3207-3213; ; doi: 10.4049/jimmunol.175.5.3207 http://www.jimmunol.org/content/175/5/3207 Downloaded from References This article cites 52 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/175/5/3207.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection1 Jacqueline R. McDermott,* Neil E. Humphreys,* Simon P. Forman,* Debra D. Donaldson,† and Richard K. Grencis2* IL-13 is a Th2-derived cytokine associated with pathological changes in asthma and ulcerative colitis. Moreover, it plays a major role in the control of gut nematode infection and associated immunopathology. The current paradigm is that these effects are due to T cell-derived IL-13. We show in this study that an innate source of IL-13, the intraepithelial NK cell, is responsible for the disruption of intestinal tissue architecture and induction of goblet cell hyperplasia that characterizes infection with the intestinal helminth Trichinella spiralis. IL-13 or IL-4R␣ (but not IL-4) null mice failed to induce intestinal pathology. Unexpectedly, SCID and athymic mice developed the same pathology found in immunocompetent mice following infection. Moreover, immunodeficient mice expressed IL-13 in the intestine, and abnormal mucosal pathology was reduced by in vivo administration of a soluble IL-13 Downloaded from antagonist. IL-13 expression was induced in non-T intraepithelial CD3؊ NK cells. Epithelial cells expressed the IL-13 signaling receptor, IL-13R␣1, and after infection, IL-4R␣. Furthermore, the soluble IL-13 decoy receptor IL-13R␣2, which regulates IL-13 responses, was also induced upon infection. These data provide the first evidence that intestinal tissue restructuring during helminth infection is an innate event dependent on IL-13 production by NK cells resident in the epithelium of the intestine. The Journal of Immunology, 2005, 175: 3207–3213. http://www.jimmunol.org/ any mucosal diseases are characterized by abnormal tinal tissue remodeling during these infections is poorly defined. In pathology, in which the tissue architecture is disrupted this study, we have sought to determine the role of IL-13 on enteric M by the actions of a variety of cytokines. Inflammatory pathology during infection with the intestinal nematode, bowel disorders induce intestinal pathology that is associated with Trichinella spiralis, in a mouse model. elevated proinflammatory cytokines (1, 2). Levels of TNF-␣ and T. spiralis occupies a niche within enterocytes of the jejunum IFN-␥ are high in Crohn’s disease (1), whereas IL-13, a Th2-type and elicits a well-characterized type 2 cytokine response orches- cytokine, drives the pathophysiology of oxazalone colitis, an ex- trated by CD4ϩ T cells (11). Following infection, CD4ϩ T cells perimental model with pathological features similar to ulcerative express IL-4, IL-5, IL-9, and IL-10 in the mesenteric lymph nodes by guest on September 29, 2021 colitis (1, 3). Further evidence points to IL-13 as the factor re- (11) and are subsequently recruited to the gut mucosa (12). In sponsible for the pathogenesis of asthma (4–7). For example, ad- addition, there is a marked eosinophilia in response to IL-5 (13) ministration of IL-13 to the airways of mice results in distinctive and a pronounced mastocytosis (14). Expulsion of the parasites asthmatic pathology of inflammatory cell infiltration, airway hy- from the intestine is dependent on mast cells recruited to the mu- perresponsiveness, and mucus hypersecretion (4, 5), while mice cosa in response to IL-4 and IL-9 (15–17). Furthermore, there are genetically deficient for IL-13 fail to develop this pathology when goblet cell hyperplasia and mucus hypersecretion that may provide challenged with model airway allergens (6). IL-13-secreting NKT mucosal protection for the host or create an inhospitable environ- cells have been implicated in the pathogenesis of both experimen- ment for the parasite (18). Moreover, distinctive changes in villus tal asthma and ulcerative colitis models (3, 8), and NK cells have and crypt architecture occur that may also be an attempt by the been implicated in the development of allergen-induced airway host to drive out the parasite by diminishing the area available for inflammation in mice (9), although it is not known whether they habitation (18). T cells are required for worm expulsion from the contribute to the responses following Th2-inducing infection. gut, but this is not IL-4 dependent, because mice genetically de- Many pathological features associated with both asthma and in- ficient for IL-4 can expel normally (19). However, expulsion is flammatory bowel disorders are identical with those induced by inhibited in mice deficient in the IL-4/IL-13 signaling molecules intestinal nematode infection of both the small and large bowel (3, IL-4R␣ or STAT6, suggesting a role for IL-13 (19, 20). IL-13 is 7, 10). These parasites induce in the host a strong Th2 response certainly critical for expulsion of another gastrointestinal nema- (10), but the etiology, in particular the role of cytokines, in intes- tode, Nippostrongylus brasiliensis, which inhabits the lumen of the small intestine (21), and resolution of Trichuris muris infection of the large bowel is also dependent on IL-13 via the production of *Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; ␣ and †Department of Respiratory Disease, Wyeth Research, Cambridge, MA 02140 TNF- (22). In addition, both T. muris (23) and N. brasiliensis Received for publication March 8, 2005. Accepted for publication June 9, 2005. (24) infection generate changes in mucosal tissue architecture, in- The costs of publication of this article were defrayed in part by the payment of page cluding villus atrophy, crypt hyperplasia, and thickening of the charges. This article must therefore be hereby marked advertisement in accordance muscularis externa. The causative factor or factors for these with 18 U.S.C. Section 1734 solely to indicate this fact. changes are unknown, although IFN-␥ has been implicated in en- 1 This work was supported by the British Medical Research Council and Wellcome terocyte proliferation during T. muris infection (23). IL-13 is also Trust. known to induce liver fibrosis in schistosomiasis (25), and is a 2 Address correspondence and reprint requests to Dr. Richard K. Grencis, Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, major contributor to pulmonary granuloma in a mouse model of Manchester M13 9PT, U.K. E-mail address: [email protected] the same disease (26). Although T cells have been assumed to be Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 3208 NK-DERIVED IL-13 INDUCES INTESTINAL PATHOLOGY the source of IL-13 during helminth infection, this has not been mented with 10% FCS, EDTA (Sigma-Aldrich), and DTT (Sigma-Al- confirmed, and the possibility of an innate source of the cytokine drich). After 15 min, tissues were shaken vigorously and supernatant con- has not been addressed. Likewise, the cellular source and target for taining epithelium was removed. This was repeated once. Epithelia were washed in HBSS twice and passed through a 40-␮m cell strainer. Cells IL-13 in asthma have yet to be definitively identified. A funda- were resuspended in either RPMI 1640 (Invitrogen Life Technologies) for mental question relates to a possible role of IL-13 in tissue remod- flow cytometry or TRIzol (Invitrogen Life Technologies) for RNA eling during intestinal helminth infections. In this study, using T. extraction. spiralis infection as a model of Th2-induced inflammation in the RNA extraction and RT-PCR small intestine, we have investigated the effect of IL-13 on enteric tissue restructuring and attempted to identify its cellular source. Epithelia or sections of jejunum were homogenized in TRIzol, and total RNA was extracted, according to the manufacturers’ protocol. Reverse- We show that IL-13 is responsible for villus atrophy and crypt and transcriptase reaction was performed using ImProm-II (Promega). The fol- goblet cell hyperplasia, and that it is not driven by the adaptive lowing primers were used to determine the level of specific mRNA: IL-13, immune response, but rather by early innate responses to infection. sense, 5Ј-ctccctctgacccttaaggag-3Ј, and antisense, 5Ј-gaaggggccgtggcgaaa Ј ␣ Ј Ј Ј SCID and athymic mice that cannot mount adaptive immune re- cag-3 ; IL-13R 1, sense, 5 -gcacgataatatggacgtgg-3 , and antisense, 5 - ttgacgacttttctccaggc-3Ј; IL-13R␣2, sense, 5Ј-atggcttttgtgcatatcagatgct-3Ј, sponses exhibit the same enteropathy as immunocompetent mice. and antisense, 5Ј-gacaaatgcgtatctt-3Ј; IL-4R␣, sense, 5Ј-gagtgagtggagtc Following infection, IL-13 is up-regulated in the jejunum of these ctagcatc-3Ј, and antisense, 5Ј-gctgaagtaacagaacaggc-3Ј; TNF-␣, sense, 5Ј- mice and is localized to the epithelial layer.
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