Phenotypic impacts of CSF1R deficiencies in humans and model organisms

Hume, David; Caruso, Melanie; Ferrari-Cestari, Michelle; Summers, Kim M.; Pridans, Clare; Irvine, Katharine M.

doi:10.1002/jlb.mr0519-143r

Cited by 94 publications

(122 citation statements)

References 162 publications

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“…Knock-in reporters, for example in the Cx3Cr1 (38) and Ccr2 loci (39) have been widelyutilized in the study of macrophage biology, but in each case the endogenous gene is knocked out. Although heterozygous mutation of Csf1r has no overt phenotypic impact in mouse, rat or human, there is no dosage compensation (1). Given the central role of CSF1R in macrophage homeostasis, a knock-out insertion is undesirable.…”

Section: Introductionmentioning

confidence: 99%

A transgenic line that reports CSF1R protein expression provides a definitive marker for the mouse mononuclear phagocyte system

Grabert

Sehgal

Irvine

et al. 2020

Preprint

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The proliferation, differentiation and survival of cells of the mononuclear phagocyte system (MPS, progenitors, monocytes, macrophages and classical dendritic cells) is controlled by signals from the macrophage colony-stimulating factor receptor (CSF1R). Cells of the MPS lineage have been identified using numerous surface markers and transgenic reporters but none is both universal and lineage-restricted. Here we report the development and characterization of a novel CSF1R reporter mouse. A Fusion Red (FRed) cassette was inserted in-frame with the C-terminus of CSF1R, separated by a T2A-cleavable linker. The insertion had no effect of CSF1R expression or function. CSF1R-FRed was expressed in monocytes and macrophages and absent from granulocytes and lymphocytes. In bone marrow, CSF1R-FRed was absent in lineage-negative hematopoietic stem cells (HSC), arguing against a direct role for CSF1R in myeloid lineage commitment. It was highly-expressed in marrow monocytes and common myeloid progenitors (CMP) but significantly lower in granulocyte-macrophage progenitors (GMP). In sections of bone marrow, CSF1R-FRed was also detected in osteoclasts, CD169+ resident macrophages and, consistent with previous mRNA analysis, in megakaryocytes. In lymphoid tissues, CSF1R-FRed highlighted diverse MPS populations including classical dendritic cells. Whole mount imaging of non-lymphoid tissues in mice with combined CSF1R-FRed/Csf1r-EGFP confirmed the restriction of CSF1R expression to MPS cells. The two markers highlight the remarkable abundance and regular distribution of tissue MPS cells including novel macrophage populations within tendon and skeletal muscle and underlying the mesothelial/serosal/capsular surfaces of every major organ. The CSF1R-FRed mouse provides a novel reporter with exquisite specificity for cells of the MPS.

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Section: Introductionmentioning

confidence: 99%

A transgenic line that reports CSF1R protein expression provides a definitive marker for the mouse mononuclear phagocyte system

Grabert

Sehgal

Irvine

et al. 2020

Preprint

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“…However, the broader impact of this approach on the innate immune system remains unclear. CSF1R is expressed by cells of the myeloid lineage 14 and therefore it is anticipated that the inhibition of CSF1R would not only affect microglia, but also have potential on-target effects in circulating and tissueresident myeloid populations, with a possible downstream immunosuppressive effect. CSF1R can be activated by two independent ligands with high affinity, the colony stimulating factor 1 (CSF-1) 15 and the recently identified interleukin 34 (IL-34) 16 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

Obst

Simon

Margarida

et al. 2020

Preprint

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The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer´s disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cellular types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF1 and interleukin 34 (IL-34).Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in neurodegenerative diseases, using the ME7 model of prion disease.Selective inhibition of IL-34 showed no effects on peripheral macrophages populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34 and that this ligand plays an important role in the modulation of microglia population during neurodegeneration. Overall, our results suggest that control of microglial response through IL-34 blockade could be a potential therapeutic approach in neurodegenerative diseases.

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“…6). Our study yields a number of 239 important observations that could only be revealed by multi-dimensional imaging using a tamoxifen-240 independent, cell type-specific fluorescent reporter model(Hume et al, 2019b(Hume et al, , 2019a. Firstly, in 241 contrast to previous reports (Gouon-Evans et al,2000, 2002), we demonstrate that Mφs encase the 242 length of elongating TEBs and are not restricted to the TEB neck.…”

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confidence: 60%

Developmental stage-specific distribution of macrophages in mouse mammary gland

Stewart

Hughes

Hume

et al. 2019

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12Mammary gland development begins in the embryo and continues throughout the reproductive life of 13 female mammals. Tissue macrophages (Mφs), dependent on signals from the Mφ colony stimulating 14 factor 1 receptor (CSF1R), have been shown to regulate the generation, regression and regeneration of 15 this organ, which is central for mammalian offspring survival. However, the distribution of Mφs in the 16 pre-and post-natal mammary gland, as it undergoes distinct phases of development and regression, is 17 unknown or has been inferred from immunostaining of thin tissue sections. Here, we used optical tissue 18 clearing and 3-dimensional imaging of mammary tissue obtained from Csf1r-EGFP mice. Whilst tissue 19Mφs were observed at all developmental phases, their abundance, morphology, localization and 20 association with luminal and basal epithelial cells exhibited stage-specific differences. Furthermore, 21 sexual dimorphism was observed at E14.5, when the male mammary bud is severed from the overlying 22 epidermis. These findings provide new insights into the localization and possible functions of 23 heterogeneous tissue Mφ populations in mammogenesis. 24

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Phenotypic impacts of CSF1R deficiencies in humans and model organisms

Cited by 94 publications

References 162 publications

A transgenic line that reports CSF1R protein expression provides a definitive marker for the mouse mononuclear phagocyte system

A transgenic line that reports CSF1R protein expression provides a definitive marker for the mouse mononuclear phagocyte system

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

Developmental stage-specific distribution of macrophages in mouse mammary gland

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