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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. Editor's summary: Radiation therapy is an effective treatment for head and neck cancer but comes with a wide range of side effects, including chronic dry mouth. McKendrick et al. investigated the role of macrophages in salivary glands to better understand their response to radiation and how they can be targeted to restore function. They identified two transcriptionally distinct CX3CR1+ macrophage subsets in salivary glands of adult mice. The gland epithelium was enriched for CD11c+CD206–CD163– macrophages, whereas CD11c–CD206+CD163+ macrophages localized to blood vessels and nerves. A mouse model of radiation-induced salivary gland injury confirmed that this treatment changes the composition and longevity of macrophage subsets at this site, but epithelium-associated CD11c+CD206–CD163– macrophages specifically are required for epithelial cell regeneration after injury. These findings provide insights into salivary gland responses to irradiation and can guide future therapies. —Christiana Fogg [ABSTRACT FROM AUTHOR]

The murine serous cavities contain a rare and enigmatic population of short‐lived F4/80loMHCII+ macrophages but what regulates their development, survival, and fate is unclear. Here, we show that mature F4/80loMHCII+ peritoneal macrophages arise after birth, but that this occurs largely independently of colonization by microbiota. Rather, microbiota specifically regulate development of a subpopulation of CD11c+ cells that express the immunoregulatory cytokine RELM‐α, are reliant on the transcription factor EGR2, and develop independently of the growth factor CSF1. Furthermore, we demonstrate that intrinsic expression of RELM‐α, a signature marker shared by CD11c+ and CD11c– F4/80loMHCII+ cavity macrophages, regulates survival and differentiation of these cells in the peritoneal cavity in a sex‐specific manner. Thus, we identify a previously unappreciated diversity in serous cavity F4/80loMHCII+ macrophages that is regulated by microbiota, and describe a novel sex and site‐specific function for RELM‐α in regulating macrophage endurance that reveals the unique survival challenge presented to monocyte‐derived macrophages by the female peritoneal environment. [ABSTRACT FROM AUTHOR]

The murine serous cavities contain a rare and enigmatic population of short-lived F4/80 lo MHCII + macrophages but what regulates their development, survival, and fate is unclear. Here, we show that mature F4/80 lo MHCII + peritoneal macrophages arise after birth, but that this occurs largely independently of colonization by microbiota. Rather, microbiota specifically regulate development of a subpopulation of CD11c + cells that express the immunoregulatory cytokine RELM-α, are reliant on the transcription factor EGR2, and develop independently of the growth factor CSF1. Furthermore, we demonstrate that intrinsic expression of RELM-α, a signature marker shared by CD11c + and CD11c - F4/80 lo MHCII + cavity macrophages, regulates survival and differentiation of these cells in the peritoneal cavity in a sex-specific manner. Thus, we identify a previously unappreciated diversity in serous cavity F4/80 lo MHCII + macrophages that is regulated by microbiota, and describe a novel sex and site-specific function for RELM-α in regulating macrophage endurance that reveals the unique survival challenge presented to monocyte-derived macrophages by the female peritoneal environment., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)