Mesothelial cell CSF1 sustains peritoneal macrophage proliferation
EUROPEAN JOURNAL OF IMMUNOLOGY
Authors: Ivanov, Stoyan; Gallerand, Alexandre; Gros, Marilyn; Stunault, Marion I.; Merlin, Johanna; Vaillant, Nathalie; Yvan-Charvet, Laurent; Guinamard, Rodolphe R.
Abstract
Macrophages play a central role during infection, inflammation and tissue homeostasis maintenance. Macrophages have been identified in all organs and their core transcriptomic signature and functions differ from one tissue to another. Interestingly, macrophages have also been identified in the peritoneal cavity and these cells have been extensively used as a model for phagocytosis, efferocytosis and polarization. Peritoneal macrophages are involved in B-cell IgA production, control of inflammation and wound healing following thermal-induced liver surface injury. These cells presumably require and interact with the omentum, where milky spot stromal cells have been proposed to secrete CSF1 (colony stimulating factor 1). Peritoneal macrophages depend on CSF1 for their generation and survival, but the identity of CSF1 producing cells inside the large peritoneal cavity remains unknown. Here we investigated peritoneal macrophage localization and their interaction with mesothelial cells, the major cell type predicted to secrete CSF1. Our data revealed that mesothelial cells produce membrane bound and secreted CSF1 that both sustain peritoneal macrophage growth.
Characterisation of a Novel Fc Conjugate of Macrophage Colony-stimulating Factor
MOLECULAR THERAPY
Authors: 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.; Hume, David A.
Abstract
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.
COA
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