TY - JOUR
T1 - Epithelial-intrinsic defects in TGFβR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis
AU - Laky, Karen
AU - Kinard, Jessica L.
AU - Li, Jenny Min
AU - Moore, Ian N.
AU - Lack, Justin
AU - Fischer, Elizabeth R.
AU - Kabat, Juraj
AU - Latanich, Rachel
AU - Zachos, Nicholas C.
AU - Limkar, Ajinkya R.
AU - Weissler, Katherine A.
AU - Thompson, Robert W.
AU - Wynn, Thomas A.
AU - Dietz, Harry C.
AU - Guerrerio, Anthony L.
AU - Frischmeyer-Guerrerio, Pamela A.
N1 - Funding Information:
Acknowledgments:W ewouldliketoacknowledgeA.Hirsch(PhysiologicInstruments)for expertassistancewithUssingChamberexperiments;J.Gu(NIAIDBioinformaticsServices)for statisticalanalyses;D.Scott (NIAID)forassistancewiththeinterpretationoftransmission electronmicroscopyimages;G.McNamaraforhelpwithimageprocessingofconfocalimages; research support specialists P . Dugan and L. Leak (NIAID Comparative Medicine Branch) for assistancewithanimalwork;D.Stephany(NIAIDFlowCytometryCore)forassistancewith MAGPIX;M.Minai(NIAID)forIHC;H.Rosenbergforexpertadviceoneosinophiltransmigration experiments,mentorship,andsupportofA.R.L.,andreviewofthemanuscript;andJ.Milnerand Y . Belkaid for critical review of the manuscript. W e also acknowledge the National Institute of DiabetesandDigestiveandKidneyDiseases–fundedIntegratedPhysiologyCoreoftheJohns HopkinsConte DigestiveDisease Basicand Translational ResearchCor eCenterforestablishing organoidculturesandprovidinggrowthfactorconditionedmedia.Funding:Thisresearchwas supportedbytheIntramuralResearchProgramoftheNIAID(ZAI001203-01toP .A.F .-G., ZAI000941toH.Rosenberg,andZAI000829andZAI001019toT .A.W .), Loeys-DietzSyndrome Foundation(toP .A.F .-G., A.L.G.,andH.C.D.),FoodAllergyResearchandEducationFoundation (FARE;P .A.F .-G.), NIHK23MentoredResearchDevelopmentA ward(K23AI091869toP .A.F .-G.), ARTrustFa culty DevelopmentA ward(toP .A.F .-G.), JohnsHopkinsUniversityClinicianScientist A ward (to P .A.F .-G.), Johns Hopkins Conte Digestive Diseases Basic and Translational Research CoreGrant(toP .A.F .-G.), GeorgeFerryYoungInvestigatorDevelopmentA ward(NorthAmerican SocietyforPediatricGastr oenter ologyHepatologyandNutritiontoA.L.G.),NIHK08Mentored ResearchDevelopmentA ward(1K08DK106463toA.L.G.),NIHP30-DK089502(toN.C.Z.andR.L.), NIHR01-AR41135-18(toH.C.D.);HHMI(toH.C.D.),WilliamS.SmilowCenterforMarfan SyndromeResearch(toH.C.D.),andNIHsharedinstrumentationgrant(1S10OD025244-01to A.L.G.).Authorcontributions:K.L.,J.L.K.,K.A.W ., A.L.G.,andP .A.F .-G. conceptualized,designed, andconductedtheexperiments;compileddata;andperformeddataanalyses.TheTgfbr1M318R knock-inmousemodelsystemoriginatedinthelaboratoryofH.C.D.J.M.L.performedqPCR assaysandcompiledandanalyzedthedata.J.L.performedbioinformaticanalysesofRNA-seq samples.E.R.F .andJ.K.performedandanalyzedtransmissionelectronmicroscopyanalyses. A.R.L.performedtransmigrationassaysandcompiledandanalyzedthedata.I.N.M.performed IHCstainingandevaluatedhistologicalimages.N.C.Z.andR.L.optimizedtheculturesystemfor esophagealorganoidsandperformedexperiments.R.W .T .andT .A.W .optimizedtheassayfor hydroxyprolinequantificationandperformedexperiments.K.L.andP .A.F .-G. wrotethe manuscriptwiththehelpofalloftheauthors.P .A.F .-G., A.L.G.,andH.C.D.initiatedandprovided fundingfortheproject.Competinginterests:Theauthorsdeclarethattheyhav eno competinginterests.Dataandmaterialsavailability:RNA-seqdatahavebeendepositedinto theGeoRepositoryAccessionnumberGSE193756.Alldataneededtoevaluatetheconclusions inthispaperarepresentinthepaperortheSupplementaryMaterials.
Funding Information:
This research was supported by the Intramural Research Program of the NIAID (ZAI001203-01 to P.A.F.-G., ZAI000941 to H. Rosenberg, and ZAI000829 and ZAI001019 to T.A.W.), Loeys-Dietz Syndrome Foundation (to P.A.F.-G., A.L.G., and H.C.D.), Food Allergy Research and Education Foundation (FARE; P.A.F.-G.), NIH K23 Mentored Research Development Award (K23AI091869 to P.A.F.-G.), ARTrust Faculty Development Award (to P.A.F.-G.), Johns Hopkins University Clinician Scientist Award (to P.A.F.-G.), Johns Hopkins Conte Digestive Diseases Basic and Translational Research Core Grant (to P.A.F.-G.), George Ferry Young Investigator Development Award (North American Society for Pediatric Gastroenterology Hepatology and Nutrition to A.L.G.), NIH K08 Mentored Research Development Award (1K08DK106463 to A.L.G.), NIH P30-DK089502 (to N.C.Z. and R.L.), NIH R01-AR41135-18 (to H.C.D.); HHMI (to H.C.D.), William S. Smilow Center for Marfan Syndrome Research (to H.C.D.), and NIH shared instrumentation grant (1S10OD025244-01 to A.L.G.).
Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
PY - 2023/1
Y1 - 2023/1
N2 - Allergic diseases are a global health challenge. Individuals harboring loss-of-function variants in transforming growth factor–β receptor (TGFβR) genes have an increased prevalence of allergic disorders, including eosinophilic esophagitis. Allergic diseases typically localize to mucosal barriers, implicating epithelial dysfunction as a cardinal feature of allergic disease. Here, we describe an essential role for TGFβ in the control of tissue-specific immune homeostasis that provides mechanistic insight into these clinical associations. Mice expressing a TGFβR1 loss-of-function variant identified in atopic patients spontaneously develop disease that clinically, immunologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis. In vivo and in vitro, TGFβR1 variant–expressing epithelial cells are hyperproliferative, fail to differentiate properly, and overexpress innate proinflammatory mediators, which persist in the absence of lymphocytes or external allergens. Together, our results support the concept that TGFβ plays a fundamental, nonredundant, epithelial cell–intrinsic role in controlling tissue-specific allergic inflammation that is independent of its role in adaptive immunity.
AB - Allergic diseases are a global health challenge. Individuals harboring loss-of-function variants in transforming growth factor–β receptor (TGFβR) genes have an increased prevalence of allergic disorders, including eosinophilic esophagitis. Allergic diseases typically localize to mucosal barriers, implicating epithelial dysfunction as a cardinal feature of allergic disease. Here, we describe an essential role for TGFβ in the control of tissue-specific immune homeostasis that provides mechanistic insight into these clinical associations. Mice expressing a TGFβR1 loss-of-function variant identified in atopic patients spontaneously develop disease that clinically, immunologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis. In vivo and in vitro, TGFβR1 variant–expressing epithelial cells are hyperproliferative, fail to differentiate properly, and overexpress innate proinflammatory mediators, which persist in the absence of lymphocytes or external allergens. Together, our results support the concept that TGFβ plays a fundamental, nonredundant, epithelial cell–intrinsic role in controlling tissue-specific allergic inflammation that is independent of its role in adaptive immunity.
UR - http://www.scopus.com/inward/record.url?scp=85145870269&partnerID=8YFLogxK
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U2 - 10.1126/sciimmunol.abp9940
DO - 10.1126/sciimmunol.abp9940
M3 - Article
C2 - 36608150
AN - SCOPUS:85145870269
SN - 2470-9468
VL - 8
JO - Science Immunology
JF - Science Immunology
IS - 79
M1 - eabp9940
ER -