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1. Typical development of synaptic and neuronal properties can proceed without microglia in the cortex and thalamus

Author

O’Keeffe, Mary, Booker, Sam A., Walsh, Darren, Li, Mosi, Henley, Chloe, Simões de Oliveira, Laura, Liu, Mingshan, Wang, Xingran, Banqueri, Maria, Ridley, Katherine, Dissanayake, Kosala N., Martinez-Gonzalez, Cristina, Craigie, Kirsty J., Vasoya, Deepali, Leah, Tom, He, Xin, Hume, David A., Duguid, Ian, Nolan, Matthew F., Qiu, Jing, Wyllie, David J. A., Dando, Owen R., Gonzalez-Sulser, Alfredo, Gan, Jian, Pridans, Clare, Kind, Peter C., and Hardingham, Giles E.

Published
2025
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3. Microglia promote anti-tumour immunity and suppress breast cancer brain metastasis

Author

Evans, Katrina T, Blake, Kerrigan, Longworth, Aaron, Coburn, Morgan A, Insua-Rodríguez, Jacob, McMullen, Timothy P, Nguyen, Quy H, Ma, Dennis, Lev, Tatyana, Hernandez, Grace A, Oganyan, Armani K, Orujyan, Davit, Edwards, Robert A, Pridans, Clare, Green, Kim N, Villalta, S Armando, Blurton-Jones, Mathew, and Lawson, Devon A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Neurosciences, Breast Cancer, Women's Health, Immunotherapy, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Mice, Animals, Humans, Female, Microglia, Breast Neoplasms, Brain Neoplasms, Brain, Treatment Outcome, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatments. Prior work has shown that brain cancers and metastases are densely infiltrated with anti-inflammatory, protumourigenic tumour-associated macrophages, but the role of brain-resident microglia remains controversial because they are challenging to discriminate from other tumour-associated macrophages. Using single-cell RNA sequencing, genetic and humanized mouse models, we specifically identify microglia and find that they play a distinct pro-inflammatory and tumour-suppressive role in BCBM. Animals lacking microglia show increased metastasis, decreased survival and reduced natural killer and T cell responses, showing that microglia are critical to promote anti-tumour immunity to suppress BCBM. We find that the pro-inflammatory response is conserved in human microglia, and markers of their response are associated with better prognosis in patients with BCBM. These findings establish an important role for microglia in anti-tumour immunity and highlight them as a potential immunotherapy target for brain metastasis.

Published
2023

5. Microglia states and nomenclature: A field at its crossroads

Author

Paolicelli, Rosa C, Sierra, Amanda, Stevens, Beth, Tremblay, Marie-Eve, Aguzzi, Adriano, Ajami, Bahareh, Amit, Ido, Audinat, Etienne, Bechmann, Ingo, Bennett, Mariko, Bennett, Frederick, Bessis, Alain, Biber, Knut, Bilbo, Staci, Blurton-Jones, Mathew, Boddeke, Erik, Brites, Dora, Brône, Bert, Brown, Guy C, Butovsky, Oleg, Carson, Monica J, Castellano, Bernardo, Colonna, Marco, Cowley, Sally A, Cunningham, Colm, Davalos, Dimitrios, De Jager, Philip L, de Strooper, Bart, Denes, Adam, Eggen, Bart JL, Eyo, Ukpong, Galea, Elena, Garel, Sonia, Ginhoux, Florent, Glass, Christopher K, Gokce, Ozgun, Gomez-Nicola, Diego, González, Berta, Gordon, Siamon, Graeber, Manuel B, Greenhalgh, Andrew D, Gressens, Pierre, Greter, Melanie, Gutmann, David H, Haass, Christian, Heneka, Michael T, Heppner, Frank L, Hong, Soyon, Hume, David A, Jung, Steffen, Kettenmann, Helmut, Kipnis, Jonathan, Koyama, Ryuta, Lemke, Greg, Lynch, Marina, Majewska, Ania, Malcangio, Marzia, Malm, Tarja, Mancuso, Renzo, Masuda, Takahiro, Matteoli, Michela, McColl, Barry W, Miron, Veronique E, Molofsky, Anna Victoria, Monje, Michelle, Mracsko, Eva, Nadjar, Agnes, Neher, Jonas J, Neniskyte, Urte, Neumann, Harald, Noda, Mami, Peng, Bo, Peri, Francesca, Perry, V Hugh, Popovich, Phillip G, Pridans, Clare, Priller, Josef, Prinz, Marco, Ragozzino, Davide, Ransohoff, Richard M, Salter, Michael W, Schaefer, Anne, Schafer, Dorothy P, Schwartz, Michal, Simons, Mikael, Smith, Cody J, Streit, Wolfgang J, Tay, Tuan Leng, Tsai, Li-Huei, Verkhratsky, Alexei, von Bernhardi, Rommy, Wake, Hiroaki, Wittamer, Valérie, Wolf, Susanne A, Wu, Long-Jun, and Wyss-Coray, Tony

Subjects
Microglia, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

Published
2022

6. Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

Author

Shabestari, Sepideh Kiani, Morabito, Samuel, Danhash, Emma Pascal, McQuade, Amanda, Sanchez, Jessica Ramirez, Miyoshi, Emily, Chadarevian, Jean Paul, Claes, Christel, Coburn, Morgan Alexandra, Hasselmann, Jonathan, Hidalgo, Jorge, Tran, Kayla Nhi, Martini, Alessandra C, Rothermich, Winston Chang, Pascual, Jesse, Head, Elizabeth, Hume, David A, Pridans, Clare, Davtyan, Hayk, Swarup, Vivek, and Blurton-Jones, Mathew

Subjects
Biochemistry and Cell Biology, Biological Sciences, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Neurosciences, Genetics, Vascular Cognitive Impairment/Dementia, Neurodegenerative, Aging, Cerebrovascular, Dementia, Alzheimer's Disease Related Dementias (ADRD), Prevention, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Cerebral Amyloid Angiopathy, Disease Models, Animal, Humans, Induced Pluripotent Stem Cells, Membrane Glycoproteins, Mice, Mice, Transgenic, Microglia, Plaque, Amyloid, Receptors, Immunologic, Alzheimer’s disease, Alzheimer’s disease co-pathologies, CP: Neuroscience, TREM2, brain calcification, cerebral amyloid angiopathy, hemorrhage, iPSC-microglia, microglia, mortality, neurovascular, Medical Physiology, Biological sciences
Abstract

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.

Published
2022

7. Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Author

Chadarevian, Jean Paul, Hasselmann, Jonathan, Lahian, Alina, Capocchi, Joia K., Escobar, Adrian, Lim, Tau En, Le, Lauren, Tu, Christina, Nguyen, Jasmine, Kiani Shabestari, Sepideh, Carlen-Jones, William, Gandhi, Sunil, Bu, Guojun, Hume, David A., Pridans, Clare, Wszolek, Zbigniew K., Spitale, Robert C., Davtyan, Hayk, and Blurton-Jones, Mathew

Published
2024
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8. Microglia protect against age-associated brain pathologies

Author

Munro, David A.D., Bestard-Cuche, Nadine, McQuaid, Conor, Chagnot, Audrey, Shabestari, Sepideh Kiani, Chadarevian, Jean Paul, Maheshwari, Upasana, Szymkowiak, Stefan, Morris, Kim, Mohammad, Mehreen, Corsinotti, Andrea, Bradford, Barry, Mabbott, Neil, Lennen, Ross J., Jansen, Maurits A., Pridans, Clare, McColl, Barry W., Keller, Annika, Blurton-Jones, Mathew, Montagne, Axel, Williams, Anna, and Priller, Josef

Published
2024
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9. Author Correction: Microglia regulate central nervous system myelin growth and integrity

Author

McNamara, Niamh B., Munro, David A. D., Bestard-Cuche, Nadine, Uyeda, Akiko, Bogie, Jeroen F. J., Hoffmann, Alana, Holloway, Rebecca K., Molina-Gonzalez, Irene, Askew, Katharine E., Mitchell, Stephen, Mungall, William, Dodds, Michael, Dittmayer, Carsten, Moss, Jonathan, Rose, Jamie, Szymkowiak, Stefan, Amann, Lukas, McColl, Barry W., Prinz, Marco, Spires-Jones, Tara L., Stenzel, Werner, Horsburgh, Karen, Hendriks, Jerome J. A., Pridans, Clare, Muramatsu, Rieko, Williams, Anna, Priller, Josef, and Miron, Veronique E.

Published
2024
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10. Microglia maintain structural integrity during fetal brain morphogenesis

Author

Lawrence, Akindé René, Canzi, Alice, Bridlance, Cécile, Olivié, Nicolas, Lansonneur, Claire, Catale, Clarissa, Pizzamiglio, Lara, Kloeckner, Benoit, Silvin, Aymeric, Munro, David A.D., Fortoul, Aurélien, Boido, Davide, Zehani, Feriel, Cartonnet, Hugues, Viguier, Sarah, Oller, Guillaume, Squarzoni, Paola, Candat, Adrien, Helft, Julie, Allet, Cécile, Watrin, Francoise, Manent, Jean-Bernard, Paoletti, Pierre, Thieffry, Denis, Cantini, Laura, Pridans, Clare, Priller, Josef, Gélot, Antoinette, Giacobini, Paolo, Ciobanu, Luisa, Ginhoux, Florent, Thion, Morgane Sonia, Lokmane, Ludmilla, and Garel, Sonia

Published
2024
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11. Microglia regulate central nervous system myelin growth and integrity

Author

McNamara, Niamh B., Munro, David A. D., Bestard-Cuche, Nadine, Uyeda, Akiko, Bogie, Jeroen F. J., Hoffmann, Alana, Holloway, Rebecca K., Molina-Gonzalez, Irene, Askew, Katharine E., Mitchell, Stephen, Mungall, William, Dodds, Michael, Dittmayer, Carsten, Moss, Jonathan, Rose, Jamie, Szymkowiak, Stefan, Amann, Lukas, McColl, Barry W., Prinz, Marco, Spires-Jones, Tara L., Stenzel, Werner, Horsburgh, Karen, Hendriks, Jerome J. A., Pridans, Clare, Muramatsu, Rieko, Williams, Anna, Priller, Josef, and Miron, Veronique E.

Published
2023
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12. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations.

Author

Rojo, Rocío, Raper, Anna, Ozdemir, Derya D, Lefevre, Lucas, Grabert, Kathleen, Wollscheid-Lengeling, Evi, Bradford, Barry, Caruso, Melanie, Gazova, Iveta, Sánchez, Alejandra, Lisowski, Zofia M, Alves, Joana, Molina-Gonzalez, Irene, Davtyan, Hayk, Lodge, Rebecca J, Glover, James D, Wallace, Robert, Munro, David AD, David, Eyal, Amit, Ido, Miron, Véronique E, Priller, Josef, Jenkins, Stephen J, Hardingham, Giles E, Blurton-Jones, Mathew, Mabbott, Neil A, Summers, Kim M, Hohenstein, Peter, Hume, David A, and Pridans, Clare

Subjects
Microglia, Monocytes, Macrophages, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Disease Models, Animal, Epidermal Growth Factor, Macrophage Colony-Stimulating Factor, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Differentiation, Cell Proliferation, Phagocytosis, Gene Expression Regulation, Sequence Deletion, Base Sequence, Regulatory Sequences, Nucleic Acid, Genes, fms, Female, Male, Embryonic Stem Cells, RAW 264.7 Cells, Inbred C57BL, Knockout, Disease Models, Animal, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Regulatory Sequences, Nucleic Acid, Genes, fms, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, MD Multidisciplinary
Abstract

The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r-/- rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.

Published
2019

13. Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Author

Mirchandani, Ananda S., Jenkins, Stephen J., Bain, Calum C., Sanchez-Garcia, Manuel A., Lawson, Hannah, Coelho, Patricia, Murphy, Fiona, Griffith, David M., Zhang, Ailiang, Morrison, Tyler, Ly, Tony, Arienti, Simone, Sadiku, Pranvera, Watts, Emily R., Dickinson, Rebecca. S., Reyes, Leila, Cooper, George, Clark, Sarah, Lewis, David, Kelly, Van, Spanos, Christos, Musgrave, Kathryn M., Delaney, Liam, Harper, Isla, Scott, Jonathan, Parkinson, Nicholas J., Rostron, Anthony J., Baillie, J. Kenneth, Clohisey, Sara, Pridans, Clare, Campana, Lara, Lewis, Philip Starkey, Simpson, A. John, Dockrell, David H., Schwarze, Jürgen, Hirani, Nikhil, Ratcliffe, Peter J., Pugh, Christopher W., Kranc, Kamil, Forbes, Stuart J., Whyte, Moira K. B., and Walmsley, Sarah R.

Published
2022
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14. Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

Author

Kiani Shabestari, Sepideh, Morabito, Samuel, Danhash, Emma Pascal, McQuade, Amanda, Sanchez, Jessica Ramirez, Miyoshi, Emily, Chadarevian, Jean Paul, Claes, Christel, Coburn, Morgan Alexandra, Hasselmann, Jonathan, Hidalgo, Jorge, Tran, Kayla Nhi, Martini, Alessandra C., Chang Rothermich, Winston, Pascual, Jesse, Head, Elizabeth, Hume, David A., Pridans, Clare, Davtyan, Hayk, Swarup, Vivek, and Blurton-Jones, Mathew

Published
2022
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15. Innate immunity champions: The diverse functions of macrophages.

Author

Biscu, Francesca, Zouzaf, Anissa, Cicia, Donatella, Pridans, Clare, and Matteoli, Gianluca

Subjects
INFLAMMATORY bowel diseases, MICROBIAL metabolites, NATURAL immunity, EXTRACELLULAR matrix, INFLAMMATION
Abstract

Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue‐specific macrophage subtypes, thereby introducing the concept of the "macrophage niche". This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue‐specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in health and disease. Macrophage metabolism is central to their ability to switch between proinflammatory and anti‐inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behavior. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to managing diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Author response: Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia

Author

Weinberger, Tobias, primary, Denise, Messerer, additional, Joppich, Markus, additional, Fischer, Maximilian, additional, Garcia Rodriguez, Clarisabel, additional, Kumaraswami, Konda, additional, Wimmeler, Vanessa, additional, Ablinger, Sonja, additional, Räuber, Saskia, additional, Fang, Jiahui, additional, Liu, Lulu, additional, Liu, Wing Han, additional, Winterhalter, Julia, additional, Lichti, Johannes, additional, Thomas, Lukas, additional, Esfandyari, Dena, additional, Percin, Guelce, additional, Matin, Sandra, additional, Hidalgo, Andrés, additional, Waskow, Claudia, additional, Engelhardt, Stefan, additional, Todica, Andrei, additional, Zimmer, Ralf, additional, Pridans, Clare, additional, Gomez Perdiguero, Elisa, additional, and Schulz, Christian, additional

Published
2024
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18. Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia

Author

Weinberger, Tobias, primary, Denise, Messerer, additional, Joppich, Markus, additional, Fischer, Maximilian, additional, Garcia Rodriguez, Clarisabel, additional, Kumaraswami, Konda, additional, Wimmler, Vanessa, additional, Ablinger, Sonja, additional, Räuber, Saskia, additional, Fang, Jiahui, additional, Liu, Lulu, additional, Liu, Wing Han, additional, Winterhalter, Julia, additional, Lichti, Johannes, additional, Thomas, Lukas, additional, Esfandyari, Dena, additional, Percin, Guelce, additional, Matin, Sandra, additional, Hidalgo, Andrés, additional, Waskow, Claudia, additional, Engelhardt, Stefan, additional, Todica, Andrei, additional, Zimmer, Ralf, additional, Pridans, Clare, additional, Gomez Perdiguero, Elisa, additional, and Schulz, Christian, additional

Published
2024
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20. Microglia protect against age-associated brain pathologies

Author

Munro, David A D, Bestard-Cuche, Nadine, McQuaid, Conor, Chagnot, Audrey, Shabestari, Sepideh Kiani, Chadarevian, Jean Paul, Maheshwari, Upasana; https://orcid.org/0000-0001-7516-3099, Szymkowiak, Stefan, Morris, Kim, Mohammad, Mehreen, Corsinotti, Andrea, Bradford, Barry, Mabbott, Neil, Lennen, Ross J, Jansen, Maurits A, Pridans, Clare, McColl, Barry W, Keller, Annika; https://orcid.org/0000-0003-1466-3633, Blurton-Jones, Mathew, Montagne, Axel, Williams, Anna, Priller, Josef, Munro, David A D, Bestard-Cuche, Nadine, McQuaid, Conor, Chagnot, Audrey, Shabestari, Sepideh Kiani, Chadarevian, Jean Paul, Maheshwari, Upasana; https://orcid.org/0000-0001-7516-3099, Szymkowiak, Stefan, Morris, Kim, Mohammad, Mehreen, Corsinotti, Andrea, Bradford, Barry, Mabbott, Neil, Lennen, Ross J, Jansen, Maurits A, Pridans, Clare, McColl, Barry W, Keller, Annika; https://orcid.org/0000-0003-1466-3633, Blurton-Jones, Mathew, Montagne, Axel, Williams, Anna, and Priller, Josef

Published
2024

21. Author Correction: Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Author

Mirchandani, Ananda S., Jenkins, Stephen J., Bain, Calum C., Sanchez-Garcia, Manuel A., Lawson, Hannah, Coelho, Patricia, Murphy, Fiona, Griffith, David M., Zhang, Ailiang, Morrison, Tyler, Ly, Tony, Arienti, Simone, Sadiku, Pranvera, Watts, Emily R., Dickinson, Rebecca. S., Reyes, Leila, Cooper, George, Clark, Sarah, Lewis, David, Kelly, Van, Spanos, Christos, Musgrave, Kathryn M., Delaney, Liam, Harper, Isla, Scott, Jonathan, Parkinson, Nicholas J., Rostron, Anthony J., Baillie, J. Kenneth, Clohisey, Sara, Pridans, Clare, Campana, Lara, Lewis, Philip Starkey, Simpson, A. John, Dockrell, David H., Schwarze, Jürgen, Hirani, Nikhil, Ratcliffe, Peter J., Pugh, Christopher W., Kranc, Kamil, Forbes, Stuart J., Whyte, Moira K. B., and Walmsley, Sarah R.

Published
2022
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23. Age related neuropathology in a novel mouse model of Adult‐onset leukoencephalopathy

Author

Shabestari, Sepideh Kiani, primary, Radhakrishnan, Hamsi, additional, Rothermich, Winston Chang, additional, Capocchi, Joia Kai, additional, Jullienne, Amandine, additional, Nguyen, Jasmine, additional, Tran, Kayla Nhi, additional, Pascual, Jesse R., additional, Martini, Alessandra Cadete, additional, Head, Elizabeth, additional, Hume, David A, additional, Pridans, Clare, additional, Obenaus, Andre, additional, Stark, Craig E.L., additional, Davtyan, Hayk, additional, and Blurton‐Jones, Mathew, additional

Published
2023
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24. The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages

Author

Scott, Charlotte L., T’Jonck, Wouter, Martens, Liesbet, Todorov, Helena, Sichien, Dorine, Soen, Bieke, Bonnardel, Johnny, De Prijck, Sofie, Vandamme, Niels, Cannoodt, Robrecht, Saelens, Wouter, Vanneste, Bavo, Toussaint, Wendy, De Bleser, Pieter, Takahashi, Nozomi, Vandenabeele, Peter, Henri, Sandrine, Pridans, Clare, Hume, David A., Lambrecht, Bart N., De Baetselier, Patrick, Milling, Simon W.F., Van Ginderachter, Jo A., Malissen, Bernard, Berx, Geert, Beschin, Alain, Saeys, Yvan, and Guilliams, Martin

Published
2018
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25. Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia

Author

Weinberger, Tobias, primary, Messerer, Denise, additional, Joppich, Markus, additional, Fischer, Max, additional, Garcia, Clarisabel, additional, Kumaraswami, Konda, additional, Wimmler, Vanessa, additional, Ablinger, Sonja, additional, Räuber, Saskia, additional, Fang, Jiahui, additional, Liu, Lulu, additional, Liu, Wing Han, additional, Winterhalter, Julia, additional, Lichti, Johannes, additional, Tomas, Lukas, additional, Esfandyari, Dena, additional, Percin, Guelce, additional, Salamanca, Sandra Martin, additional, Hidalgo, Andres, additional, Waskow, Claudia, additional, Engelhardt, Stefan, additional, Todica, Andrei, additional, Zimmer, Ralf, additional, Pridans, Clare, additional, Gomez-Perdiguero, Elisa, additional, and Schulz, Christian, additional

Published
2023
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26. Synthesis and Development of Highly Selective Pyrrolo[2,3-d]pyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form

Author

Aarhus, Thomas Ihle, primary, Bjørnstad, Frithjof, additional, Wolowczyk, Camilla, additional, Larsen, Kristin Uhlving, additional, Rognstad, Line, additional, Leithaug, Trygve, additional, Unger, Anke, additional, Habenberger, Peter, additional, Wolf, Alexander, additional, Bjørkøy, Geir, additional, Pridans, Clare, additional, Eickhoff, Jan, additional, Klebl, Bert, additional, Hoff, Bård H., additional, and Sundby, Eirik, additional

Published
2023
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28. Microglia regulate central nervous system myelin growth and integrity

Author

McNamara, Niamh B., primary, Munro, David A. D., additional, Bestard-Cuche, Nadine, additional, Uyeda, Akiko, additional, Bogie, Jeroen F. J., additional, Hoffmann, Alana, additional, Holloway, Rebecca K., additional, Molina-Gonzalez, Irene, additional, Askew, Katharine E., additional, Mitchell, Stephen, additional, Mungall, William, additional, Dodds, Michael, additional, Dittmayer, Carsten, additional, Moss, Jonathan, additional, Rose, Jamie, additional, Szymkowiak, Stefan, additional, Amann, Lukas, additional, McColl, Barry W., additional, Prinz, Marco, additional, Spires-Jones, Tara L., additional, Stenzel, Werner, additional, Horsburgh, Karen, additional, Hendriks, Jerome J. A., additional, Pridans, Clare, additional, Muramatsu, Rieko, additional, Williams, Anna, additional, Priller, Josef, additional, and Miron, Veronique E., additional

Published
2022
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29. Characterisation of a Novel Fc Conjugate of Macrophage Colony-stimulating Factor

Author

Gow, Deborah J, Sauter, Kristin A, Pridans, Clare, Moffat, Lindsey, Sehgal, Anuj, Stutchfield, Ben M, Raza, Sobia, Beard, Philippa M, Tsai, Yi Ting, Bainbridge, Graeme, Boner, Pamela L, Fici, Greg, Garcia-Tapia, David, Martin, Roger A, Oliphant, Theodore, Shelly, John A, Tiwari, Raksha, Wilson, Thomas L, Smith, Lee B, Mabbott, Neil A, and Hume, David A

Published
2014
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31. CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury.

Author

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., and Emmerson, Elaine

Subjects
SALIVARY glands, MACROPHAGES, REGENERATION (Biology), ONTOGENY, HEAD & neck cancer, EPITHELIAL cells, DOSE-response relationship (Radiation)
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. 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]

Published
2023
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32. Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain: Microglia and prion disease

Author

Bradford, Barry, McGuire, Lynne, Hume, David A., Pridans, Clare, and Mabbott, Neil

Subjects
reactive astrocyte, prion disease, neurodegeneration, Microglia, CNS
Abstract

Prion diseases are transmissible, neurodegenerative disorders associated with misfolding of the prion protein. Previous studies show that reduction of microglia accelerates CNS prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1rΔFIRE mice, the deletion of an enhancer within Csf1r specifically blocks microglia development, however, their brains develop normally and show none of the deficits reported in other microglia-deficient models. Csf1rΔFIRE mice were used as a refined model in which to study the impact of microglia-deficiency on CNS prion disease. Although Csf1rΔFIRE mice succumbed to CNS prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhancedphagocytosis of neuronal contents and unfolded protein responses. Our data suggest that rather than simply phagocytosing and destroying prions, the microglia instead provide host-protection during CNS prion disease and restrict the harmful activities of reactive astrocytes.

Published
2022
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33. Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia

Author

Diffner, Eva, Beck, Dominik, Gudgin, Emma, Thoms, Julie A.I., Knezevic, Kathy, Pridans, Clare, Foster, Sam, Goode, Debbie, Lim, Weng Khong, Boelen, Lies, Metzeler, Klaus H., Micklem, Gos, Bohlander, Stefan K., Buske, Christian, Burnett, Alan, Ottersbach, Katrin, Vassiliou, George S., Olivier, Jake, Wong, Jason W.H., Göttgens, Berthold, Huntly, Brian J., and Pimanda, John E.

Published
2013
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36. CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration following radiation-induced injury

Author

McKendrick, John G, primary, Jones, Gareth-Rhys, additional, Elder, Sonia S, additional, Mercer, Ella, additional, Magalhaes, Marlene S, additional, Rocchi, Cecilia, additional, Hegarty, Lizi M, additional, Johnson, Amanda L, additional, Schneider, Christoph, additional, Becher, Burkhard, additional, Pridans, Clare, additional, Mabbott, Neil A, additional, Liu, Zhaoyuan, additional, Ginhoux, Florent, additional, Bajenoff, Marc, additional, Gentek, Rebecca, additional, Bain, Calum C, additional, and Emmerson, Elaine, additional

Published
2022
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37. A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

Author

Stables, Jennifer, Green, Emma, Sehgal, Anuj, Patkar, Omkar, Keshvari, Sahar, Taylor, Isis, Ashkroft, Maisie, Grabert, Kathleen, Wollscheid-Lengeling, Evi, Szymkowiak, Stefan, McColl, Barry, Adamson, Antony, Humphreys, Neil, Mueller, Werner, Starobova, Hana, Vetter, Irinia, Shabestari, Sepideh Kiani, Blurton-Jones, Matthew, Summers, Kim, Irvine, Katharine, Pridans, Clare, Hume, David, Stables, Jennifer, Green, Emma, Sehgal, Anuj, Patkar, Omkar, Keshvari, Sahar, Taylor, Isis, Ashkroft, Maisie, Grabert, Kathleen, Wollscheid-Lengeling, Evi, Szymkowiak, Stefan, McColl, Barry, Adamson, Antony, Humphreys, Neil, Mueller, Werner, Starobova, Hana, Vetter, Irinia, Shabestari, Sepideh Kiani, Blurton-Jones, Matthew, Summers, Kim, Irvine, Katharine, Pridans, Clare, and Hume, David

Abstract

Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.

Published
2022

38. Microglia states and nomenclature: A field at its crossroads.

Author

Paolicelli, Rosa C., Sierra, Amanda, Stevens, Beth, Tremblay, Marie-Eve, Aguzzi, Adriano, Ajami, Bahareh, Amit, Ido, Audinat, Etienne, Bechmann, Ingo, Bennett, Mariko, Bennett, Frederick, Bessis, Alain, Biber, Knut, Bilbo, Staci, Blurton-Jones, Mathew, Boddeke, Erik, Brites, Dora, Brône, Bert, Brown, Guy C., Butovsky, Oleg, Carson, Monica J., Castellano, Bernardo, Colonna, Marco, Cowley, Sally A., Cunningham, Colm, Davalos, Dimitrios, De Jager, Philip L., de Strooper, Bart, Denes, Adam, Eggen, Bart J. L., Eyo, Ukpong, Galea, Elena, Garel, Sonia, Ginhoux, Florent, Glass, Christopher K., Gokce, Ozgun, Gomez-Nicola, Diego, González, Berta, Gordon, Siamon, Graeber, Manuel B., Greenhalgh, Andrew D., Gressens, Pierre, Greter, Melanie, Gutmann, David H., Haass, Christian, Heneka, Michael, Heppner, Frank L., Hong, Soyon, Hume, David A., Jung, Steffen, Kettenmann, Helmut, Kipnis, Jonathan, Koyama, Ryuta, Lemke, Greg, Lynch, Marina, Majewska, Ania, Malcangio, Marzia, Malm, Tarja, Mancuso, Renzo, Masuda, Takahiro, Matteoli, Michela, McColl, Barry W., Miron, Veronique E., Molofsky, Anna Victoria, Monje, Michelle, Mracsko, Eva, Nadjar, Agnes, Neher, Jonas J., Neniskyte, Urte, Neumann, Harald, Noda, Mami, Peng, Bo, Peri, Francesca, Perry, V. Hugh, Popovich, Phillip G., Pridans, Clare, Priller, Josef, Prinz, Marco, Ragozzino, Davide, Ransohoff, Richard M., Salter, Michael W., Schaefer, Anne, Schafer, Dorothy P., Schwartz, Michal, Simons, Mikael, Smith, Cody J., Streit, Wolfgang J., Tay, Tuan Leng, Tsai, Li-Huei, Verkhratsky, Alexei, von Bernhardi, Rommy, Wake, Hiroaki, Wittamer, Valérie, Wolf, Susanne A., Wu, Long-Jun, Wyss-Coray, Tony, Paolicelli, Rosa C., Sierra, Amanda, Stevens, Beth, Tremblay, Marie-Eve, Aguzzi, Adriano, Ajami, Bahareh, Amit, Ido, Audinat, Etienne, Bechmann, Ingo, Bennett, Mariko, Bennett, Frederick, Bessis, Alain, Biber, Knut, Bilbo, Staci, Blurton-Jones, Mathew, Boddeke, Erik, Brites, Dora, Brône, Bert, Brown, Guy C., Butovsky, Oleg, Carson, Monica J., Castellano, Bernardo, Colonna, Marco, Cowley, Sally A., Cunningham, Colm, Davalos, Dimitrios, De Jager, Philip L., de Strooper, Bart, Denes, Adam, Eggen, Bart J. L., Eyo, Ukpong, Galea, Elena, Garel, Sonia, Ginhoux, Florent, Glass, Christopher K., Gokce, Ozgun, Gomez-Nicola, Diego, González, Berta, Gordon, Siamon, Graeber, Manuel B., Greenhalgh, Andrew D., Gressens, Pierre, Greter, Melanie, Gutmann, David H., Haass, Christian, Heneka, Michael, Heppner, Frank L., Hong, Soyon, Hume, David A., Jung, Steffen, Kettenmann, Helmut, Kipnis, Jonathan, Koyama, Ryuta, Lemke, Greg, Lynch, Marina, Majewska, Ania, Malcangio, Marzia, Malm, Tarja, Mancuso, Renzo, Masuda, Takahiro, Matteoli, Michela, McColl, Barry W., Miron, Veronique E., Molofsky, Anna Victoria, Monje, Michelle, Mracsko, Eva, Nadjar, Agnes, Neher, Jonas J., Neniskyte, Urte, Neumann, Harald, Noda, Mami, Peng, Bo, Peri, Francesca, Perry, V. Hugh, Popovich, Phillip G., Pridans, Clare, Priller, Josef, Prinz, Marco, Ragozzino, Davide, Ransohoff, Richard M., Salter, Michael W., Schaefer, Anne, Schafer, Dorothy P., Schwartz, Michal, Simons, Mikael, Smith, Cody J., Streit, Wolfgang J., Tay, Tuan Leng, Tsai, Li-Huei, Verkhratsky, Alexei, von Bernhardi, Rommy, Wake, Hiroaki, Wittamer, Valérie, Wolf, Susanne A., Wu, Long-Jun, and Wyss-Coray, Tony

Abstract

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

Published
2022

39. Microglia states and nomenclature: A field at its crossroads.

Author

Paolicelli, Rosa RC, Sierra, Amanda, Stevens, Beth, Tremblay, Marie-Eve, Aguzzi, Adriano, Ajami, Bahareh, Amit, Ido, Audinat, Etienne, Bechmann, Ingo, Bennett, Mariko, Bennett, Frederick, Bessis, Alain, Biber, Knut, Bilbo, Staci, Blurton-Jones, Mathew, Boddeke, Erik, Brites, Dora, Brône, Bert, Brown, Guy C, Butovsky, Oleg, Carson, Monica J, Castellano, Bernardo, Colonna, Marco, Cowley, Sally A, Cunningham, Colm, Davalos, Dimitrios, De Jager, Philip L, De Strooper, Bart, Denes, Adam, Eggen, Bart BJL, Eyo, Ukpong, Galea, Elena, Garel, Sonia, Ginhoux, Florent, Glass, Christopher K, Gokce, Ozgun, Gomez-Nicola, Diego, González, Berta, Gordon, Siamon, Graeber, Manuel MB, Greenhalgh, Andrew AD, Gressens, Pierre, Greter, Melanie, Gutmann, David DH, Haass, Christian, Heneka, Michael MT, Heppner, Frank FL, Hong, Soyon, Hume, David DA, Jung, Steffen, Kettenmann, Helmut, Kipnis, Jonathan, Koyama, Ryuta, Lemke, Greg, Lynch, Marina, Majewska, Ania, Malcangio, Marzia, Malm, Tarja, Mancuso, Renzo, Masuda, Takahiro, Matteoli, Michela, McColl, Barry W, Miron, Veronique E, Molofsky, Anna Victoria, Monje, Michelle, Mracsko, Eva, Nadjar, Agnes, Neher, Jonas JJ, Neniskyte, Urte, Neumann, Frank Harald, Noda, Mami, Peng, Bo, Peri, Francesca, Perry, Hugh VH, Popovich, Phillip PG, Pridans, Clare, Priller, Josef, Prinz, Marco, Ragozzino, Davide, Ransohoff, Richard M, Salter, Michael W, Schaefer, Anne, Schafer, Dorothy P, Schwartz, Michal, Simons, Mikael, Smith, Cody J, Streit, Wolfgang WJ, Tay, Tuan Leng, Tsai, Li-Huei, Verkhratsky, Alexei, von Bernhardi, Rommy, Wake, Hiroaki, Wittamer, Valérie, Wolf, Susanne A, Wu, Long-Jun, Wyss-Coray, Tony, Paolicelli, Rosa RC, Sierra, Amanda, Stevens, Beth, Tremblay, Marie-Eve, Aguzzi, Adriano, Ajami, Bahareh, Amit, Ido, Audinat, Etienne, Bechmann, Ingo, Bennett, Mariko, Bennett, Frederick, Bessis, Alain, Biber, Knut, Bilbo, Staci, Blurton-Jones, Mathew, Boddeke, Erik, Brites, Dora, Brône, Bert, Brown, Guy C, Butovsky, Oleg, Carson, Monica J, Castellano, Bernardo, Colonna, Marco, Cowley, Sally A, Cunningham, Colm, Davalos, Dimitrios, De Jager, Philip L, De Strooper, Bart, Denes, Adam, Eggen, Bart BJL, Eyo, Ukpong, Galea, Elena, Garel, Sonia, Ginhoux, Florent, Glass, Christopher K, Gokce, Ozgun, Gomez-Nicola, Diego, González, Berta, Gordon, Siamon, Graeber, Manuel MB, Greenhalgh, Andrew AD, Gressens, Pierre, Greter, Melanie, Gutmann, David DH, Haass, Christian, Heneka, Michael MT, Heppner, Frank FL, Hong, Soyon, Hume, David DA, Jung, Steffen, Kettenmann, Helmut, Kipnis, Jonathan, Koyama, Ryuta, Lemke, Greg, Lynch, Marina, Majewska, Ania, Malcangio, Marzia, Malm, Tarja, Mancuso, Renzo, Masuda, Takahiro, Matteoli, Michela, McColl, Barry W, Miron, Veronique E, Molofsky, Anna Victoria, Monje, Michelle, Mracsko, Eva, Nadjar, Agnes, Neher, Jonas JJ, Neniskyte, Urte, Neumann, Frank Harald, Noda, Mami, Peng, Bo, Peri, Francesca, Perry, Hugh VH, Popovich, Phillip PG, Pridans, Clare, Priller, Josef, Prinz, Marco, Ragozzino, Davide, Ransohoff, Richard M, Salter, Michael W, Schaefer, Anne, Schafer, Dorothy P, Schwartz, Michal, Simons, Mikael, Smith, Cody J, Streit, Wolfgang WJ, Tay, Tuan Leng, Tsai, Li-Huei, Verkhratsky, Alexei, von Bernhardi, Rommy, Wake, Hiroaki, Wittamer, Valérie, Wolf, Susanne A, Wu, Long-Jun, and Wyss-Coray, Tony

Abstract

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2022

42. A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

Author

Stables, Jennifer, primary, Green, Emma K., additional, Sehgal, Anuj, additional, Patkar, Omkar L., additional, Keshvari, Sahar, additional, Taylor, Isis, additional, Ashcroft, Maisie E., additional, Grabert, Kathleen, additional, Wollscheid-Lengeling, Evi, additional, Szymkowiak, Stefan, additional, McColl, Barry W., additional, Adamson, Antony, additional, Humphreys, Neil E., additional, Mueller, Werner, additional, Starobova, Hana, additional, Vetter, Irina, additional, Shabestari, Sepideh Kiani, additional, Blurton-Jones, Matthew M., additional, Summers, Kim M., additional, Irvine, Katharine M., additional, Pridans, Clare, additional, and Hume, David A., additional

Published
2022
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43. Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

Author

Mirchandani, Ananda S, primary, Jenkins, Stephen J, additional, Bain, Calum C, additional, Lawson, Hannah, additional, Coelho, Patricia, additional, Murphy, Fiona, additional, Griffith, David, additional, Zhang, Ailiang, additional, Sanchez-Garcia, Manuel A, additional, Reyes, Leila, additional, Morrison, Tyler, additional, Arienti, Simone, additional, Sadiku, Pranvera, additional, Watts, Emily, additional, Dickinson, Rebecca, additional, Clark, Sarah, additional, Ly, Tony, additional, Lewis, David, additional, Kelly, Van, additional, Spanos, Christos, additional, Musgrave, Kathyrn, additional, Delaney, Liam, additional, Harper, Isla, additional, Scott, Jonathan, additional, Parkinson, Nicholas, additional, Rostron, Anthony, additional, Baillie, J Kenneth, additional, Clohisey, Sara Mary Rose, additional, Pridans, Clare, additional, Campana, Lara, additional, Starkey, Philip, additional, Simpson, A John, additional, Dockrell, David, additional, Schwarze, Jurgen, additional, Hirani, Nikhil, additional, Ratcliffe, Peter, additional, Pugh, Christopher, additional, Kranc, Kamil, additional, Forbes, Stuart, additional, Whyte, Moira, additional, and Walmsley, Sarah, additional

Published
2022
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44. A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant-negative impact on CSF1R signaling

Author

Stables, Jennifer, primary, Green, Emma K., additional, Sehgal, Anuj, additional, Patkar, Omkar, additional, Keshvari, Sahar, additional, Taylor, Isis, additional, Ashcroft, Maisie E., additional, Grabert, Kathleen, additional, Wollscheid-Lengeling, Evi, additional, Szymkowiak, Stefan, additional, McColl, Barry W., additional, Adamson, Antony, additional, Humphreys, Neil E., additional, Mueller, Werner, additional, Starobova, Hana, additional, Vetter, Irina, additional, Shabestari, Sepideh Kiani, additional, Blurton-Jones, Matthew M., additional, Summers, Kim M., additional, Irvine, Katharine M., additional, Pridans, Clare, additional, and Hume, David A., additional

Published
2021
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46. Siglec-15 is a rapidly internalised cell-surface antigen expressed by acute myeloid leukaemia cells

Author

Cao, Huan, Neerincx, Andreas, de Bono, Bernard, Lakner, Ursula, Huntington, Catherine, Elvin, John, Gudgin, Emma, Pridans, Clare, Vickers, Mark A, Huntly, Brian J, Trowsdale, John, and Barrow, Alexander David

Subjects
hemic and lymphatic diseases, respiratory system
Abstract

Siglec-15 has recently been identified as mediating a critical tumour checkpoint, augmenting the expression and function of PD-L1. We raised a monoclonal antibody, A9E8, specific for Siglec-15 using phage display. A9E8 detected cell-surface expression of Siglec-15 on myeloid blasts from both cell lines and peripheral blood cells from 9/12 AML patients. By contrast, there was minimal expression on leucocytes from healthy donors suggesting targeting Siglec-15 may have significant therapeutic advantages over its fellow Siglec CD33. After binding, A9E8 was rapidly internalized (t1/2, 180sec) into K562 cells. Antibodies to Siglec-15 hold therapeutic potential for treatment of AML.

Published
2021
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47. Complete microglia deficiency accelerates prion disease without enhancing CNS prion accumulation

Author

Bradford, Barry, McGuire, Lynne, Hume, David A., Pridans, Clare, and Mabbott, Neil

Subjects
nervous system, animal diseases, nervous system diseases
Abstract

Prion diseases are transmissible, neurodegenerative disorders to which there are no cures. Previous studies show that reduction of microglia accelerates prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1rΔFIRE mice, the deletion of an enhancer within Csf1r specifically blocks microglia development, however, their brains develop normally with none of the deficits reported in other microglia-deficient models. Csf1rΔFIRE mice were used as a refined model to study the impact of microglia-deficiency on CNS prion disease. Although Csf1rΔFIRE mice succumbed to prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced synaptic pruning and unfolded protein responses. Our data suggest that rather than engulfing and degrading prions, the microglia instead provide neuroprotection and restrict the harmful activities of reactive astrocytes.

Published
2021
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48. CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

Author

Keshvari, Sahar, primary, Caruso, Melanie, additional, Teakle, Ngari, additional, Batoon, Lena, additional, Sehgal, Anuj, additional, Patkar, Omkar L., additional, Ferrari-Cestari, Michelle, additional, Snell, Cameron E., additional, Chen, Chen, additional, Stevenson, Alex, additional, Davis, Felicity M., additional, Bush, Stephen J., additional, Pridans, Clare, additional, Summers, Kim M., additional, Pettit, Allison R., additional, Irvine, Katharine M., additional, and Hume, David A., additional

Published
2021
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49. CNS macrophage populations differentially rely on an intronic Csf1r enhancer for their development

Author

Munro, David, Bradford, Barry, Mariani, Samanta, Hampton, David, Vink, Chris, Chandran, Siddharthan, Hume, David, Pridans, Clare, and Priller, Josef

Subjects
food and beverages
Abstract

The central nervous system hosts parenchymal macrophages, known as microglia, and non-parenchymal macrophages, collectively termed border-associated macrophages (BAMs). Microglia and BAMs emerge following the early lineage divergence of a common embryonic progenitor in the yolk sac. Microglia, but not BAMs, were reported to be absent in mice lacking a conserved Csf1r enhancer, the fms-intronic regulatory element (FIRE). However, it is unknown whether this mutation also impacts BAM arrival and/or maintenance. Here, we show that intracerebroventricular macrophages, including Kolmer’s epiplexus macrophages, are absent in embryonic and adult Csf1rΔFIRE/ΔFIRE mice. Stromal choroid plexus BAMs are also considerably reduced. We demonstrate that macrophages arrive in brain ventricles from embryonic day 10.5, and can traverse ventricular walls to enter ventricles in embryonic slice cultures. In Csf1rΔFIRE/ΔFIRE embryos, the arrival of both primitive microglia and intracerebroventricular macrophages was eliminated, while the arrival of cephalic mesenchyme and stromal choroid plexus BAMs was only partially restricted. Our results indicate that microglia and BAMs differentially rely on FIRE shortly after their developmental programmes diverge, and support the concept that intracerebroventricular macrophages are microglia-like cells.

Published
2020
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50. CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

Author

Keshvari, Sahar, Caruso, Melanie, Teakle, Ngari, Batoon, Lena, Sehgal, Anuj, Patkar, Omkar L., Ferrari-Cestari, Michelle, Snell, Cameron E., Chen, Chen, Stevenson, Alex, Davis, Felicity M., Bush, Stephen J., Pridans, Clare, Summers, Kim M., Pettit, Allison R., Irvine, Katharine M., Hume, David A., and Barsh, Gregory S.

Subjects
Male, Cancer Research, Heredity, Somatic cell, medicine.medical_treatment, Gene Expression, QH426-470, Monocytes, Diagnostic Radiology, Gene Knockout Techniques, White Blood Cells, 0302 clinical medicine, Bone Marrow, Genes, Reporter, Animal Cells, Medicine and Health Sciences, Inbreeding, Insulin-Like Growth Factor I, Receptor, Genetics (clinical), Bone Marrow Transplantation, 0303 health sciences, Microglia, Liver Diseases, Radiology and Imaging, Musculoskeletal Development, Gene Expression Regulation, Developmental, Mononuclear phagocyte system, Pulmonary Imaging, Cell biology, Insulin-Like Growth Factor Binding Proteins, Haematopoiesis, medicine.anatomical_structure, Liver, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Osteopetrosis, Hepatocyte, Female, Rats, Transgenic, Cellular Types, Stem cell, Research Article, Imaging Techniques, Immune Cells, Transgene, Immunology, Bone Marrow Cells, Gastroenterology and Hepatology, Biology, Research and Analysis Methods, Andrology, 03 medical and health sciences, Diagnostic Medicine, Genetics, medicine, Animals, Humans, Progenitor cell, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Blood Cells, Macrophages, Growth factor, Biology and Life Sciences, Lipid metabolism, Cell Biology, Embryo, Mammalian, Lipid Metabolism, Embryonic stem cell, Musculoskeletal Abnormalities, Rats, Fatty Liver, Disease Models, Animal, Bone marrow, 030217 neurology & neurosurgery, Granulocytes
Abstract

Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation., Author summary Monocytes and macrophages are cells of the innate immune system produced by the bone marrow that can be recruited into tissues to support defense against infection and repair following injury. So-called resident macrophages are abundant in every tissue in the body. Their numbers are controlled by a hormone-like growth factor called macrophage colony-stimulating factor (CSF1). Mutations in the surface receptor (CSF1R) that enables macrophages to respond to CSF1 lead to the loss of tissue macrophages. Human patients born with CSF1R mutations may die in infancy or suffer severe developmental abnormalities in the skeleton and brain. In this study we report the effects of the loss of tissue macrophages on postnatal growth and development in a rat model of CSF1R deficiency. In this model there was a global loss of resident macrophages, severe postnatal growth defects, failure of development of multiple organs including the liver and early death. The effects of the mutation could be rescued completely by transfer of normal bone marrow cells into the peritoneal cavity at weaning permitting long term survival and even fertility. The results indicate that postnatal expansion of tissue macrophage populations is essential for normal development.

Published
2020
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