@article{ae55a6fa1a40412782c00ceca7ba9846,
title = "CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury",
abstract = "The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant immune cell in the salivary glands and are attractive therapeutic targets due to their unrivaled capacity to drive tissue repair. Yet, the nature and role of macrophages in salivary gland homeostasis and how they may contribute to tissue repair after injury are not well understood. Here, we show that at least two phenotypically and transcriptionally distinct CX3CR1+ macrophage populations are present in the adult salivary gland, which occupy anatomically distinct niches. CD11c+CD206–CD163– macrophages typically associate with gland epithelium, whereas CD11c−CD206+CD163+ macrophages associate with blood vessels and nerves. Using a suite of complementary fate mapping systems, we show that there are highly dynamic changes in the ontogeny and composition of salivary gland macrophages with age. Using an in vivo model of radiation-induced salivary gland injury combined with genetic or antibody-mediated depletion of macrophages, we demonstrate an essential role for macrophages in clearance of cells with DNA damage. Furthermore, we show that epithelial-associated macrophages are indispensable for effective tissue repair and gland function after radiation-induced injury, with their depletion resulting in reduced saliva production. Our data, therefore, provide a strong case for exploring the therapeutic potential of manipulating macrophages to promote tissue repair and thus minimize salivary gland dysfunction after radiotherapy.",
author = "Mckendrick, {John g.} and Gareth-Rhys Jones and Elder, {Sonia s.} and Erin Watson and Wouter T{\textquoteright}jonck and Ella Mercer and Magalhaes, {Marlene s.} and Cecilia Rocchi and Hegarty, {Lizi m.} and Johnson, {Amanda l.} and Christoph Schneider and Burkhard Becher and Clare Pridans and Neil Mabbott and Zhaoyuan Liu and Florent Ginhoux and Marc Bajenoff and Rebecca Gentek and Bain, {Calum c.} and Elaine Emmerson",
note = "Funding Information: Acknowledgments:W ewouldliketothankA.Corsinotti(CRMMulti-omicsFacility),F .Rossi, andtheCRMFlowCytometryFacility,theCIRFlowCytometryFa cility ,M.Vermerenandthe CRMImagingFa cility ,theCRMtissueculturefacility,andtheCRMandLFRUniversityof Edinburghanimalfacilities.W ewouldliketothankS.ForbesandS.Pearson-Cra venforcritical reading of the manuscript and D. Withers for advice regarding T cell staining. This study is dedicatedtothememoryofourcolleagueK.Lavin-Thomson.ServierMedicalArt,pro vided by Servier,wasusedforthegenerationofsomefigures,licensedunderaCreativeCommons Attribution3.0unportedlicense.Funding:J.G.M.isfundedbyUKRI/MRCgrantMR/W004763/1 and the University of Edinburgh Chancellor{\textquoteright}s Fellowship studentship; G.-R.J. is funded by a W ellcome Trus tClinicalCareerDevelopmentFellowship(220725/Z/20/Z);S.S.E.,E.M.,andL.M.H. arefundedbyW ellcome Trustgrant108906/Z/15/Z;E.W .isfundedbyUKRI/BBSRCgrantBB/ T00875X/1;W .T .isfundedbyW ellcome Trust/Roy al Societygrant(206234/Z/17/Z)andUKRI PostdoctoralGuaranteeFellowshipEP/X025071/1;C.R.isfundedbyUKRI/MRCgrantMR/ S005544/1;N.M.isfundedbyUKRI/MRCgrantMR/S000763/1andUKRI/BBSRCgrantBBS/E/D/ 10002071;Z.L.isfundedbytheNationalNaturalScienceFoundationofChina(31900630and 32070880);M.S.M.andR.G.arefundedbytheKennedyTrustforRheumatologyResearch,andR. G. is also funded bya Chancellor{\textquoteright}s Fellowship from the Universityof Edinburgh; C.C.B. is funded byaSirHenryDaleFellowshipjointlyawardedbytheW ellcome TrustandbytheRoyalSociety (grantnumber206234/Z/17/Z);E.E.isfundedbyUKRI/MRCgrantMR/S005544/1andbya Funding Information: We would like to thank A. Corsinotti (CRM Multi-omics Facility), F. Rossi, and the CRM Flow Cytometry Facility, the CIR Flow Cytometry Facility, M. Vermeren and the CRM Imaging Facility, the CRM tissue culture facility, and the CRM and LFR University of Edinburgh animal facilities. We would like to thank S. Forbes and S. Pearson-Craven for critical reading of the manuscript and D. Withers for advice regarding T cell staining. This study is dedicated to the memory of our colleague K. Lavin-Thomson. Servier Medical Art, provided by Servier, was used for the generation of some figures, licensed under a Creative Commons Attribution 3.0 unported license. J.G.M. is funded by UKRI/MRC grant MR/W004763/1 and the University of Edinburgh Chancellor{\textquoteright}s Fellowship studentship; G.-R.J. is funded by a Wellcome Trust Clinical Career Development Fellowship (220725/Z/20/Z); S.S.E., E.M., and L.M.H. are funded by Wellcome Trust grant 108906/Z/15/Z; E.W. is funded by UKRI/BBSRC grant BB/ T00875X/1; W.T. is funded by Wellcome Trust/Royal Society grant (206234/Z/17/Z) and UKRI Postdoctoral Guarantee Fellowship EP/X025071/1; C.R. is funded by UKRI/MRC grant MR/ S005544/1; N.M. is funded by UKRI/MRC grant MR/S000763/1 and UKRI/BBSRC grant BBS/E/D/ 10002071; Z.L. is funded by the National Natural Science Foundation of China (31900630 and 32070880); M.S.M. and R.G. are funded by the Kennedy Trust for Rheumatology Research, and R. G. is also funded by a Chancellor{\textquoteright}s Fellowship from the University of Edinburgh; C.C.B. is funded by a Sir Henry Dale Fellowship jointly awarded by the Wellcome Trust and by the Royal Society (grant number 206234/Z/17/Z); E.E. is funded by UKRI/MRC grant MR/S005544/1 and by a Chancellor{\textquoteright}s Fellowship from the University of Edinburgh. C.C.B. and E.E. have additional joint funding from the Wellcome Trust/ISSF3 Strategic Funds, the Royal Society (RGS\R2\202277), and the MRC Neuroimmunology Award Scheme (MR/W004763/1). For the purpose of open access, we have applied a Creative Commons Attribution (CC BY) license to any author-accepted manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2023 American Association for the Advancement of Science. All rights reserved.",
year = "2023",
month = nov,
day = "3",
doi = "10.1126/sciimmunol.add4374",
language = "English",
volume = "8",
journal = "Science Immunology",
issn = "2470-9468",
publisher = "American Association for the Advancement of Science",
number = "89",
}