We have produced an Fc conjugate of colony-stimulating factor (CSF) 1 with an
improved circulating half-life. CSF1-Fc retained its macrophage growth-promoting
activity, and did not induce proinflammatory cytokines in vitro.
Treatment with CSF1-Fc did not produce adverse effects in mice or pigs. The
impact of CSF1-Fc was examined using the Csf1r-enhanced green
fluorescent protein (EGFP) reporter gene in MacGreen mice. Administration of
CSF1-Fc to mice drove extensive infiltration of all tissues by
Csf1r-EGFP positive macrophages. The main consequence was
hepatosplenomegaly, associated with proliferation of hepatocytes. Expression
profiles of the liver indicated that infiltrating macrophages produced candidate
mediators of hepatocyte proliferation including urokinase, tumor necrosis
factor, and interleukin 6. CSF1-Fc also promoted osteoclastogenesis and produced
pleiotropic effects on other organ systems, notably the testis, where
CSF1-dependent macrophages have been implicated in homeostasis. However, it did
not affect other putative CSF1 targets, notably intestine, where Paneth cell
numbers and villus architecture were unchanged. CSF1 has therapeutic potential
in regenerative medicine in multiple organs. We suggest that the CSF1-Fc
conjugate retains this potential, and may permit daily delivery by injection
rather than continuous infusion required for the core molecule.
Background & AimsLiver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice.MethodsWe measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles.ResultsSerum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells.ConclusionsSerum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury.
Growth hormone controls somatic growth in mammals by regulating the production of IGF-1, which is predominantly made by the liver. The development of cells within the MPS is controlled by the lineage-specific growth factor M-CSF (CSF-1). In this review, we summarize the role of CSF-1-dependent macrophages in somatic growth and organogenesis. We propose that macrophages are the major extrahepatic source of IGF-1 and that a surge of CSF-1 production contributes to the control of postnatal growth and organ maturation. Accordingly, CSF-1 may be considered a part of the GH/IGF-1 axis.
Highlights► The active region of porcine CSF-1 and full length CSF-1R have been cloned. ► Biological activity of porcine CSF-1 has been demonstrated. ► The cross species reactivity of IL-34 has been investigated. ► Both mouse and human IL-34 are biologically active on the pig CSF-1R. ► CSF-1 and IL-34 structure analysis of species-specific activity has been performed.
Faecal samples were collected from 57 clinically healthy kittens presented for initial vaccination, in the UK. Routine bacteriological examination identified Salmonella species in one and Campylobacter species in five samples. Polymerase chain reaction (PCR) detected the presence of Campylobacter species in a further four samples. Routine parasitological examination revealed Toxocara species ova in nine (including four kittens stated to have been administered an anthelmintic) and Isospora species in four samples. No Giardia or Cryptosporidium species were detected by routine methods. A Giardia species enzyme-linked immunosorbent assay (ELISA) test kit designed for use in cats was positive in three kittens. A similar test kit designed for use in humans was negative in all samples and produced negative results even when known positive samples were tested. Potentially pathogenic enteric organisms were detected in 19 kittens by routine methods and 26 (prevalence 45%) by all methods. The high prevalence in asymptomatic kittens highlights the possibility that the detection of these organisms in kittens with gastrointestinal disease may be an incidental finding.
Hypoadrenocorticism is a well-described endocrinopathy in dogs that results from deficient production and secretion of glucocorticoids and/or mineralocorticoids. Although hyperkalaemia, hyponatraemia and hypochloraemia are the most common electrolyte disturbances, hypercalcaemia also occurs in approximately 30 per cent of cases. The pathogenesis of hypercalcaemia in dogs with hypoadrenocorticism is unknown. This case series reports ionised calcium, parathyroid hormone, parathyroid hormone-related protein and vitamin D metabolite concentrations that were measured in eight dogs with concurrent hypercalcaemia and hypoadrenocorticism. Ionised calcium was increased in five of seven dogs with hypercalcaemia associated with hypoadrenocorticism. Parathyroid hormone, parathyroid hormone-related protein and 1,25 dihydroxyvitamin D concentrations were within their reference ranges in seven of eight dogs, six of seven cases and six of seven dogs, respectively. This case series highlights that hypercalcaemia associated with hypoadrenocorticism is rarely associated with increases in plasma parathyroid hormone, parathyroid hormone-related protein or serum 1,25 dihydroxyvitamin D concentrations.
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