Macrophage Lab | Katharine Irvine and David Hume

@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}

}