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CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury


McKendrick, John G; Jones, Gareth-Rhys; Elder, Sonia S; Watson, Erin; T'Jonck, Wouter; Mercer, Ella; Magalhaes, Marlene S; Rocchi, Cecilia; Hegarty, Lizi M; Johnson, Amanda L; Schneider, Christoph; Becher, Burkhard; Pridans, Clare; Mabbott, Neil; Liu, Zhaoyuan; Ginhoux, Florent; Bajenoff, Marc; Gentek, Rebecca; Bain, Calum C; Emmerson, Elaine (2023). CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury. Science Immunology, 8(89):eadd4374.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Language:English
Date:3 November 2023
Deposited On:30 Jan 2024 14:25
Last Modified:30 Jun 2024 01:38
Publisher:American Association for the Advancement of Science
ISSN:2470-9468
OA Status:Closed
Publisher DOI:https://doi.org/10.1126/sciimmunol.add4374
PubMed ID:37922341