Macrophage Lab | Katharine Irvine and David Hume

@article{pmid37167456,

title = {Macrophage deficiency in CSF1R-knockout rat embryos does not compromise placental or embryo development},

author = {David A Hume and Ngari Teakle and Sahar Keshvari and Katharine M Irvine},

doi = {10.1093/jleuko/qiad052},

issn = {1938-3673},

year  = {2023},

date = {2023-05-01},

journal = {J Leukoc Biol},

abstract = {Macrophages are an abundant cell population in the placenta and developing embryo and appear to be involved in processes of vascularisation, morphogenesis, organogenesis and hematopoiesis. The proliferation, differentiation and survival is dependent upon signals from the macrophage colony-stimulating factor receptor, CSF1R. Aside from the role in macrophages, Csf1r mRNA is highly-expressed in placental trophoblasts. To explore the function of macrophages and Csf1r in placental and embryonic development, we analysed the impact of homozygous Csf1r null mutation (Csf1rko) in the rat. In late gestation, IBA1+ macrophages were abundant in control embryos in all tissues including the placenta and greatly-reduced in the Csf1rko. CSF1R was also detected in stellate macrophage-like cells and in neurons using anti-CSF1R antibody but was undetectable in trophoblasts. However, the neuronal signal was not abolished in the Csf1rko. CD163 was most abundant in cells forming the centre of erythroblastic islands in the liver and was also CSF1R-dependent. Despite the substantial reduction in macrophage numbers, we detected no effect of the Csf1rko on development of the placenta or any organs, the relative abundance of vascular elements (CD31 staining) or cell proliferation (Ki67 staining). The loss of CD163+ erythroblastic island macrophages in the liver was not associated with anemia or any reduction in the proliferative activity in the liver, but there was a premature expansion of CD206+cells, presumptive precursors of liver sinusoidal endothelial cells. We suggest that many functions of macrophages in development of the placenta and embryo can be provided by other cell types in their absence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37059596,

title = {Intraperitoneal transfer of wild-type bone marrow repopulates tissue macrophages in the Csf1r knockout rat without contributing to monocytopoiesis},

author = {Anuj Sehgal and Dylan Carter-Cusack and Sahar Keshvari and Omkar Patkar and Stephen Huang and Kim M Summers and David A Hume and Katharine M Irvine},

doi = {10.1002/eji.202250312},

issn = {1521-4141},

year  = {2023},

date = {2023-04-01},

journal = {Eur J Immunol},

pages = {e2250312},

abstract = {Homozygous null mutation of the Csf1r gene (Csf1rko) in rats leads to the loss of most tissue macrophage populations and pleiotropic impacts on postnatal growth and organ maturation, leading to early mortality. The phenotype can be reversed by intraperitoneal transfer of WT BM cells (BMT) at weaning. Here, we used a Csf1r-mApple transgenic reporter to track the fate of donor-derived cells. Following BMT into Csf1rko recipients, mApple cells restored IBA1 tissue macrophage populations in every tissue. However, monocytes, neutrophils, and B cells in the BM, blood, and lymphoid tissues remained of recipient (mApple ) origin. An mApple cell population expanded in the peritoneal cavity and invaded locally in the mesentery, fat pads, omentum, and diaphragm. One week after BMT, distal organs contained foci of mApple , IBA1 immature progenitors that appeared to proliferate, migrate, and differentiate locally. We conclude that rat BM contains progenitor cells that are able to restore, replace, and maintain all tissue macrophage populations in a Csf1rko rat directly without contributing to the BM progenitor or blood monocyte populations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36630758,

title = {Fibrillin-1 and asprosin, novel players in metabolic syndrome},

author = {Kim M Summers and Stephen J Bush and Margaret R Davis and David A Hume and Sahar Keshvari and Jennifer A West},

doi = {10.1016/j.ymgme.2022.106979},

issn = {1096-7206},

year  = {2023},

date = {2023-01-01},

journal = {Mol Genet Metab},

volume = {138},

number = {1},

pages = {106979},

abstract = {Fibrillin-1 is a major component of the extracellular microfibrils, where it interacts with other extracellular matrix proteins to provide elasticity to connective tissues, and regulates the bioavailability of TGFβ family members. A peptide consisting of the C-terminal 140 amino acids of fibrillin-1 has recently been identified as a glucogenic hormone, secreted from adipose tissue during fasting and targeting the liver to release glucose. This fragment, called asprosin, also signals in the hypothalamus to stimulate appetite. Asprosin levels are correlated with many of the pathologies indicative of metabolic syndrome, including insulin resistance and obesity. Previous studies and reviews have addressed the therapeutic potential of asprosin as a target in obesity, diabetes and related conditions without considering mechanisms underlying the relationship between generation of asprosin and expression of the much larger fibrillin-1 protein. Profibrillin-1 undergoes obligatory cleavage at the cell surface as part of its assembly into microfibrils, producing the asprosin peptide as well as mature fibrillin-1. Patterns of FBN1 mRNA expression are inconsistent with the necessity for regulated release of asprosin. The asprosin peptide may be protected from degradation in adipose tissue. We present evidence for an alternative possibility, that asprosin mRNA is generated independently from an internal promoter within the 3' end of the FBN1 gene, which would allow for regulation independent of fibrillin-synthesis and is more economical of cellular resources. The discovery of asprosin opened exciting possibilities for treatment of metabolic syndrome related conditions, but there is much to be understood before such therapies could be introduced into the clinic.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36327947,

title = {Serum CC-Chemokine Ligand 2 Is Associated with Visceral Adiposity but Not Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease},

author = {Michelle Ferrari-Cestari and Satomi Okano and Preya J Patel and Leigh U Horsfall and Sahar Keshvari and David A Hume and Suzanne Williams and Anthony Russell and Elizabeth E Powell and Katharine M Irvine},

doi = {10.1159/000527784},

issn = {1421-9875},

year  = {2023},

date = {2023-01-01},

journal = {Dig Dis},

volume = {41},

number = {3},

pages = {439--446},

abstract = {BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver as a consequence of metabolic perturbations associated with obesity, type 2 diabetes, dyslipidemia, and insulin resistance. People with NAFLD may develop metabolic and cardiovascular complications and/or liver-related complications, especially fibrosis and hepatocellular carcinoma, associated with high morbidity and mortality. Due to the high and increasing prevalence of NAFLD, there is an urgent need to identify people at risk of developing liver fibrosis and complications. CC-chemokine ligand 2 (CCL2) is chemokine that attracts inflammatory monocytes to stressed or injured tissues. Infiltrating inflammatory monocytes and CCL2 are strongly implicated in the pathogenesis of liver disease in animal models; however, evidence in patient cohorts is conflicting.nnMETHODS: We investigated associations between circulating CCL2 and clinical parameters, including fibrosis assessed by liver stiffness measurement, in a cohort of 250 NAFLD patients. We also measured fatty acid binding protein 2 (FABP2), a putative biomarker of intestinal permeability in patients with liver disease, since pro-inflammatory gut-derived microbial products may induce inflammatory chemokines such as CCL2.nnRESULTS: Serum CCL2 levels were weakly associated with liver stiffness, but the association was no longer significant after accounting for age, diabetes, and BMI in a multivariable model. Consistent with this, girth and BMI were the strongest predictors of elevated circulating CCL2. Serum FABP2 was weakly, but significantly, correlated with CCL2, and negatively correlated with estimated glomerular filtration rate.nnCONCLUSION: Circulating CCL2 and FABP2 are associated with NAFLD comorbidities but not liver disease progression in patients with NAFLD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36197652,

title = {CSF1R as a Therapeutic Target in Bone Diseases: Obvious but Not so Simple},

author = {David A Hume and Lena Batoon and Anuj Sehgal and Sahar Keshvari and Katharine M Irvine},

doi = {10.1007/s11914-022-00757-4},

issn = {1544-2241},

year  = {2022},

date = {2022-12-01},

journal = {Curr Osteoporos Rep},

volume = {20},

number = {6},

pages = {516--531},

abstract = {PURPOSE OF REVIEW: The purpose of the review is to summarize the expression and function of CSF1R and its ligands in bone homeostasis and constraints on therapeutic targeting of this axis.nnRECENT FINDINGS: Bone development and homeostasis depends upon interactions between mesenchymal cells and cells of the mononuclear phagocyte lineage (MPS), macrophages, and osteoclasts (OCL). The homeostatic interaction is mediated in part by the systemic and local production of growth factors, macrophage colony-stimulating factor (CSF1), and interleukin 34 (IL34) that interact with a receptor (CSF1R) expressed exclusively by MPS cells and their progenitors. Loss-of-function mutations in CSF1 or CSF1R lead to loss of OCL and macrophages and dysregulation of postnatal bone development. MPS cells continuously degrade CSF1R ligands via receptor-mediated endocytosis. As a consequence, any local or systemic increase or decrease in macrophage or OCL abundance is rapidly reversible. In principle, both CSF1R agonists and antagonists have potential in bone regenerative medicine but their evaluation in disease models and therapeutic application needs to carefully consider the intrinsic feedback control of MPS biology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35333324,

title = {A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling},

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

doi = {10.1242/dev.200237},

issn = {1477-9129},

year  = {2022},

date = {2022-04-01},

journal = {Development},

volume = {149},

number = {8},

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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35169835,

title = {Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease},

author = {Sahar Keshvari and Berit Genz and Ngari Teakle and Melanie Caruso and Michelle F Cestari and Omkar L Patkar and Brian W C Tse and Kamil A Sokolowski and Hilmar Ebersbach and Julia Jascur and Kelli P A MacDonald and Gregory Miller and Grant A Ramm and Allison R Pettit and Andrew D Clouston and Elizabeth E Powell and David A Hume and Katharine M Irvine},

doi = {10.1242/dmm.049387},

issn = {1754-8411},

year  = {2022},

date = {2022-02-01},

journal = {Dis Model Mech},

abstract = {Resident and recruited macrophages control the development and proliferation of the liver. We showed previously in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, utilizing a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodeling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{keshvari_csf1r-dependent_2021b,

title = {CSF1R-dependent macrophages control postnatal somatic growth and organ maturation},

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

editor = {Gregory S. Barsh},

url = {https://dx.plos.org/10.1371/journal.pgen.1009605},

doi = {10.1371/journal.pgen.1009605},

issn = {1553-7404},

year  = {2021},

date = {2021-06-01},

urldate = {2021-10-21},

journal = {PLOS Genetics},

volume = {17},

number = {6},

pages = {e1009605},

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, CD43 

 hi 

 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{hume_mononuclear_2021,

title = {The Mononuclear Phagocyte System of the Rat},

author = {David A. Hume and Melanie Caruso and Sahar Keshvari and Omkar L. Patkar and Anuj Sehgal and Stephen J. Bush and Kim M. Summers and Clare Pridans and Katharine M. Irvine},

url = {http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.2100136},

doi = {10.4049/jimmunol.2100136},

issn = {0022-1767, 1550-6606},

year  = {2021},

date = {2021-05-01},

urldate = {2021-10-21},

journal = {The Journal of Immunology},

volume = {206},

number = {10},

pages = {2251--2263},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{keshvari_csf1r-dependent_2021,

title = {CSF1R-dependent macrophages control postnatal somatic growth and organ maturation},

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

url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009605},

doi = {10.1371/journal.pgen.1009605},

issn = {1553-7404},

year  = {2021},

date = {2021-01-01},

urldate = {2021-08-06},

journal = {PLOS Genetics},

volume = {17},

number = {6},

pages = {e1009605},

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.},

note = {Publisher: Public Library of Science},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{patkar_analysis_2021,

title = {Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations},

author = {O. L. Patkar and M. Caruso and N. Teakle and S. Keshvari and S. J. Bush and C. Pridans and A. Belmer and K. M. Summers and K. M. Irvine and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85099616799&doi=10.1016%2fj.nbd.2021.105268&partnerID=40&md5=b1a09a2930f62a2ec0fc08fd98da6279},

doi = {10.1016/j.nbd.2021.105268},

issn = {09699961},

year  = {2021},

date = {2021-01-01},

journal = {Neurobiology of Disease},

volume = {151},

abstract = {Mutations in the human CSF1R gene have been associated with dominant and recessive forms of neurodegenerative disease. Here we describe the impacts of Csf1r mutation in the rat on development of the brain. Diffusion imaging indicated small reductions in major fiber tracts that may be associated in part with ventricular enlargement. RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats. There was no evidence of region or sex-specific expression of microglia-associated transcripts. Other than the microglial signature, Csf1rko had no effect on any neuronal or region-specific transcript cluster. Expression of markers of oligodendrocytes, astrocytes, dopaminergic neurons and Purkinje cells was minimally affected. However, there were defects in dendritic arborization of doublecortin-positive neurogenic precursors and expression of poly-sialylated neural cell adhesion molecule (PS-NCAM) in the dentate gyrus of the hippocampus. Heterozygous Csf1rko rats had no detectable brain phenotype. We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy. © 2021 The Authors},

note = {Publisher: Academic Press Inc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{irvine_analysis_2020,

title = {Analysis of the impact of CSF‐1 administration in adult rats using a novel textitCsf1r ‐mApple reporter gene},

author = {Katharine M. Irvine and Melanie Caruso and Michelle Ferrari Cestari and Gemma M. Davis and Sahar Keshvari and Anuj Sehgal and Clare Pridans and David A. Hume},

url = {https://onlinelibrary.wiley.com/doi/10.1002/JLB.MA0519-149R},

doi = {10.1002/JLB.MA0519-149R},

issn = {0741-5400, 1938-3673},

year  = {2020},

date = {2020-02-01},

urldate = {2021-10-21},

journal = {Journal of Leukocyte Biology},

volume = {107},

number = {2},

pages = {221--235},

keywords = {},

pubstate = {published},

tppubtype = {article}

}