{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T01:39:04Z","timestamp":1789781944559,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011296","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000}}],"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC11181_A02"],"award-info":[{"award-number":["CRC11181_A02"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Gastrointestinal helminths are a major health threat worldwide. Alternatively activated macrophages (AAMs) have been shown to contribute to host protection during secondary helminth infections. AAMs express effector molecules that depend on activation of the IL-4- or IL-13-induced transcription factor signal transducer and activator of transcription 6 (STAT6). However, the specific role of STAT6-regulated genes like Arginase-1 (Arg1) from AAMs or STAT6-regulated genes in other cell types for host protection remains unclear. To address this point, we generated mice expressing STAT6 only in macrophages (Mac-STAT6 mouse). In the model of <jats:italic>Heligmosomoides polygyrus bakeri<\/jats:italic> (<jats:italic>Hpb<\/jats:italic>) infection, Mac-STAT6 mice could not trap larvae in the submucosa of the small intestine after secondary infection. Further, mice lacking Arg1 in hematopoietic and endothelial cells were still protected from secondary <jats:italic>Hpb<\/jats:italic> infection. On the other hand, specific deletion of IL-4\/IL-13 in T cells blunted AAM polarization, activation of intestinal epithelial cells (IECs) and protective immunity. Deletion of IL-4R\u03b1 on IEC also caused loss of larval trapping while AAM polarization remained intact. These results show that Th2-dependent and STAT6-regulated genes in IECs are required and AAMs are not sufficient for protection against secondary <jats:italic>Hpb<\/jats:italic> infection by mechanisms that remain to be investigated.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011296","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T18:11:42Z","timestamp":1680718302000},"page":"e1011296","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Th2-dependent STAT6-regulated genes in intestinal epithelial cells mediate larval trapping during secondary Heligmosomoides polygyrus bakeri infection"],"prefix":"10.1371","volume":"19","author":[{"given":"Stefanie","family":"Westermann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Schubart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Dietschmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirstin","family":"Castiglione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Radtke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-0639","authenticated-orcid":true,"given":"David","family":"Voehringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,4,5]]},"reference":[{"issue":"9521","key":"ppat.1011296.ref001","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1016\/S0140-6736(06)68653-4","article-title":"Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm","volume":"367","author":"J Bethony","year":"2006","journal-title":"The Lancet"},{"issue":"3","key":"ppat.1011296.ref002","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1179\/136485909X398212","article-title":"Geohelminth infection and re-infection after chemotherapy among slum-dwelling children in Durban, South Africa","volume":"103","author":"CC Appleton","year":"2009","journal-title":"Ann Trop Med Parasitol"},{"issue":"4","key":"ppat.1011296.ref003","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/cpmo.34","article-title":"The Study of Host Immune Responses Elicited by the Model Murine Hookworms Nippostrongylus brasiliensis and Heligmosomoides polygyrus.","volume":"7","author":"T Bouchery","year":"2017","journal-title":"Curr Protoc Mouse Biol."},{"key":"ppat.1011296.ref004","doi-asserted-by":"crossref","DOI":"10.1002\/0471142735.im1912s55","article-title":"Animal model of Nippostrongylus brasiliensis and Heligmosomoides polygyrus.","author":"M Camberis","year":"2003","journal-title":"Jr.Curr Protoc Immunol"},{"issue":"5","key":"ppat.1011296.ref005","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S1471-4906(03)00101-7","article-title":"The immune response to parasitic helminths: insights from murine models","volume":"24","author":"WC Gause","year":"2003","journal-title":"Trends Immunol"},{"issue":"4","key":"ppat.1011296.ref006","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.4049\/jimmunol.172.4.2424","article-title":"Peripheral CD4 T cells rapidly accumulate at the host: parasite interface during an inflammatory Th2 memory response","volume":"172","author":"M Morimoto","year":"2004","journal-title":"J Immunol"},{"issue":"8","key":"ppat.1011296.ref007","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/nm1451","article-title":"Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites.","volume":"12","author":"RM Anthony","year":"2006","journal-title":"Nat Med"},{"issue":"35","key":"ppat.1011296.ref008","doi-asserted-by":"crossref","first-page":"eaau3814","DOI":"10.1126\/sciimmunol.aau3814","article-title":"RELMa-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection","volume":"4","author":"B Krljanac","year":"2019","journal-title":"Sci Immunol"},{"issue":"48","key":"ppat.1011296.ref009","doi-asserted-by":"crossref","first-page":"E5169","DOI":"10.1073\/pnas.1412663111","article-title":"Basophil-mediated protection against gastrointestinal helminths requires IgE-induced cytokine secretion","volume":"111","author":"C Schwartz","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"17","key":"ppat.1011296.ref010","doi-asserted-by":"crossref","first-page":"6644","DOI":"10.1073\/pnas.1112268109","article-title":"Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines","volume":"109","author":"MR Hepworth","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"ppat.1011296.ref011","doi-asserted-by":"crossref","first-page":"5315","DOI":"10.1128\/IAI.67.10.5315-5323.1999","article-title":"Trapping and immobilization of Nippostrongylus brasiliensis larvae at the site of inoculation in primary infections of interleukin-5 transgenic mice","volume":"67","author":"CM Daly","year":"1999","journal-title":"Infect Immun"},{"issue":"7293","key":"ppat.1011296.ref012","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/nature08900","article-title":"Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity","volume":"464","author":"DR Neill","year":"2010","journal-title":"Nature"},{"issue":"4","key":"ppat.1011296.ref013","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.smim.2014.06.003","article-title":"Host protective roles of type 2 immunity: parasite killing and tissue repair, flip sides of the same coin.","volume":"26","author":"JE Allen","year":"2014","journal-title":"Semin Immunol."},{"issue":"17","key":"ppat.1011296.ref014","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1182\/blood-2010-02-271981","article-title":"Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2","volume":"116","author":"S Huber","year":"2010","journal-title":"Blood"},{"issue":"4","key":"ppat.1011296.ref015","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.4049\/jimmunol.170.4.1789","article-title":"The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone 1\/resistin-like molecule alpha gene expression by a STAT6 and CCAAT\/enhancer-binding protein-dependent mechanism","volume":"170","author":"AM Stutz","year":"2003","journal-title":"J Immunol"},{"issue":"11","key":"ppat.1011296.ref016","doi-asserted-by":"crossref","first-page":"e1007423","DOI":"10.1371\/journal.ppat.1007423","article-title":"Ym1 induces RELMalpha and rescues IL-4Ralpha deficiency in lung repair during nematode infection","volume":"14","author":"TE Sutherland","year":"2018","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1011296.ref017","doi-asserted-by":"crossref","first-page":"e1000371","DOI":"10.1371\/journal.ppat.1000371","article-title":"Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis","volume":"5","author":"JT Pesce","year":"2009","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1011296.ref018","doi-asserted-by":"crossref","first-page":"e1000393","DOI":"10.1371\/journal.ppat.1000393","article-title":"Retnla (relmalpha\/fizz1) suppresses helminth-induced Th2-type immunity.","volume":"5","author":"JT Pesce","year":"2009","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1011296.ref019","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1084\/jem.20082048","article-title":"Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung","volume":"206","author":"MG Nair","year":"2009","journal-title":"J Exp Med"},{"issue":"4","key":"ppat.1011296.ref020","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1128\/IAI.01479-15","article-title":"Comparison of RELMalpha and RELMbeta Single- and Double-Gene-Deficient Mice Reveals that RELMalpha Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection","volume":"84","author":"G Chen","year":"2016","journal-title":"Infect Immun"},{"issue":"4","key":"ppat.1011296.ref021","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/JLB.4A0917-369RR","article-title":"Hematopoietic cell-derived RELMalpha regulates hookworm immunity through effects on macrophages","volume":"104","author":"HM Batugedara","year":"2018","journal-title":"J Leukoc Biol"},{"issue":"2","key":"ppat.1011296.ref022","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41385-018-0107-3","article-title":"Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths","volume":"12","author":"C Schubart","year":"2019","journal-title":"Mucosal Immunol"},{"issue":"19","key":"ppat.1011296.ref023","doi-asserted-by":"crossref","first-page":"14255","DOI":"10.1074\/jbc.C000129200","article-title":"A gain-of-function mutation in STAT6","volume":"275","author":"C Daniel","year":"2000","journal-title":"J Biol Chem"},{"issue":"28","key":"ppat.1011296.ref024","doi-asserted-by":"crossref","first-page":"17634","DOI":"10.1074\/jbc.273.28.17634","article-title":"Mutational analysis of the STAT6 SH2 domain","volume":"273","author":"T Mikita","year":"1998","journal-title":"J Biol Chem"},{"issue":"4","key":"ppat.1011296.ref025","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1002\/eji.201948313","article-title":"Modulation of the humoral immune response by constitutively active STAT6 expression in murine B cells","volume":"50","author":"P Haase","year":"2020","journal-title":"Eur J Immunol"},{"issue":"4","key":"ppat.1011296.ref026","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/0014-4894(91)90074-7","article-title":"Heligmosomoides polygyrus: CD4+ but not CD8+ T cells regulate the IgE response and protective immunity in mice","volume":"73","author":"JF Urban","year":"1991","journal-title":"Exp Parasitol"},{"issue":"5","key":"ppat.1011296.ref027","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/s41590-019-0352-y","article-title":"The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation","volume":"20","author":"FR Svedberg","year":"2019","journal-title":"Nat Immunol"},{"issue":"3","key":"ppat.1011296.ref028","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.4049\/jimmunol.1401645","article-title":"Antibody-mediated trapping of helminth larvae requires CD11b and Fcgamma receptor I","volume":"194","author":"J Esser-von Bieren","year":"2015","journal-title":"J Immunol"},{"issue":"12","key":"ppat.1011296.ref029","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/ni.1671","article-title":"Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens","volume":"9","author":"KC El Kasmi","year":"2008","journal-title":"Nat Immunol"},{"issue":"4","key":"ppat.1011296.ref030","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.chom.2017.09.006","article-title":"Epithelial-Cell-Derived Phospholipase A(2) Group 1B Is an Endogenous Anthelmintic.","volume":"22","author":"LJ Entwistle","year":"2017","journal-title":"Cell Host Microbe"},{"issue":"3","key":"ppat.1011296.ref031","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.pt.2004.01.004","article-title":"Alternatively activated macrophages during parasite infections","volume":"20","author":"W Noel","year":"2004","journal-title":"Trends Parasitol"},{"issue":"12","key":"ppat.1011296.ref032","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1084\/jem.20130761","article-title":"The skin is an important bulwark of acquired immunity against intestinal helminths","volume":"210","author":"K Obata-Ninomiya","year":"2013","journal-title":"J Exp Med"},{"issue":"9","key":"ppat.1011296.ref033","doi-asserted-by":"crossref","first-page":"4675","DOI":"10.4049\/jimmunol.154.9.4675","article-title":"IL-4 treatment can cure established gastrointestinal nematode infections in immunocompetent and immunodeficient mice","volume":"154","author":"JF Urban","year":"1995","journal-title":"J Immunol"},{"issue":"11","key":"ppat.1011296.ref034","doi-asserted-by":"crossref","first-page":"6078","DOI":"10.4049\/jimmunol.167.11.6078","article-title":"Cutting edge: IL-4 receptor expression by non-bone marrow-derived cells is required to expel gastrointestinal nematode parasites","volume":"167","author":"JF Urban","year":"2001","journal-title":"J Immunol"},{"issue":"2","key":"ppat.1011296.ref035","doi-asserted-by":"crossref","first-page":"948","DOI":"10.4049\/jimmunol.171.2.948","article-title":"Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves","volume":"171","author":"A Zhao","year":"2003","journal-title":"J Immunol"},{"issue":"13","key":"ppat.1011296.ref036","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1084\/jem.20091268","article-title":"Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection","volume":"206","author":"DR Herbert","year":"2009","journal-title":"J Exp Med"},{"issue":"4","key":"ppat.1011296.ref037","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.immuni.2022.03.009","article-title":"Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C","volume":"55","author":"M Zhao","year":"2022","journal-title":"Immunity"},{"issue":"37","key":"ppat.1011296.ref038","doi-asserted-by":"crossref","first-page":"13596","DOI":"10.1073\/pnas.0404034101","article-title":"RELM\u00df\/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract","volume":"101","author":"D Artis","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"ppat.1011296.ref039","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/mi.2014.101","article-title":"Conditional IL-4\/IL-13-deficient mice reveal a critical role of innate immune cells for protective immunity against gastrointestinal helminths","volume":"8","author":"K Oeser","year":"2015","journal-title":"Mucosal Immunol"},{"issue":"4","key":"ppat.1011296.ref040","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1023\/A:1008942828960","article-title":"Conditional gene targeting in macrophages and granulocytes using LysMcre mice","volume":"8","author":"BE Clausen","year":"1999","journal-title":"Transgenic Research"},{"issue":"8","key":"ppat.1011296.ref041","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.4049\/jimmunol.157.8.3220","article-title":"Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice","volume":"157","author":"K Takeda","year":"1996","journal-title":"J Immunol"},{"issue":"5","key":"ppat.1011296.ref042","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S1074-7613(04)00107-4","article-title":"Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology","volume":"20","author":"DR Herbert","year":"2004","journal-title":"Immunity"},{"issue":"7","key":"ppat.1011296.ref043","doi-asserted-by":"crossref","first-page":"3590","DOI":"10.4049\/jimmunol.1401155","article-title":"T cell-derived IL-4\/IL-13 protects mice against fatal Schistosoma mansoni infection independently of basophils","volume":"193","author":"C Schwartz","year":"2014","journal-title":"J Immunol"},{"issue":"10","key":"ppat.1011296.ref044","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1084\/jem.189.10.1565","article-title":"Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type 2-mediated responses.","volume":"189","author":"G McKenzie","year":"1999","journal-title":"J Exp Med"},{"issue":"3","key":"ppat.1011296.ref045","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.4049\/jimmunol.151.3.1235","article-title":"Anti-cytokine antibodies as carrier proteins. Prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes","volume":"151","author":"FD Finkelman","year":"1993","journal-title":"J Immunol"},{"issue":"12","key":"ppat.1011296.ref046","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1002\/eji.202170126","article-title":"Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition).","volume":"51","author":"A Cossarizza","year":"2021","journal-title":"Eur J Immunol"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1011296","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011296","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T17:39:54Z","timestamp":1681753194000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011296"}},"subtitle":[],"editor":[{"given":"Meera Goh","family":"Nair","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,4,5]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1011296","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.ppat.1011296","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,5]]}}}