title: Cell-Surface and Secreted Isoforms of CSF-1 Exert Opposing Roles in Macrophage-Mediated Neural Damage in Cx32-Deficient Mice.
abstract: Previous studies in myelin-mutant mouse models of the inherited and incurable nerve disorder, Charcot-Marie-Tooth (CMT) neuropathy, have demonstrated that low-grade secondary inflammation implicating phagocytosing macrophages amplifies demyelination, Schwann cell dedifferentiation and perturbation of axons. The cytokine colony stimulating factor-1 (CSF-1) acts as an important regulator of these macrophage-related disease mechanisms, as genetic and pharmacologic approaches to block the CSF-1/CSF-1R signaling result in a significant alleviation of pathological alterations in mutant peripheral nerves. In mouse models of CMT1A and CMT1X, as well as in human biopsies, CSF-1 is predominantly expressed by endoneurial fibroblasts, which are closely associated with macrophages, suggesting local stimulatory mechanisms. Here we investigated the impact of cell-surface and secreted isoforms of CSF-1 on macrophage-related disease in connexin32-deficient (Cx32def) mice, a mouse model of CMT1X. Our present observations suggest that the secreted proteoglycan isoform (spCSF-1) is predominantly expressed by fibroblasts, whereas the membrane-spanning cell-surface isoform (csCSF-1) is expressed by macrophages. Using crossbreeding approaches to selectively restore or overexpress distinct isoforms in CSF-1-deficient (osteopetrotic) Cx32def mice, we demonstrate that both isoforms equally regulate macrophage numbers dose-dependently. However, spCSF-1 mediates macrophage activation and macrophage-related neural damage, whereas csCSF-1 inhibits macrophage activation and attenuates neuropathy. These results further corroborate the important role of secondary inflammation in mouse models of CMT1 and might identify specific targets for therapeutic approaches to modulate innate immune reactions.
  
  
  CONCLUSIONS
  Mouse models of Charcot-Marie-Tooth neuropathy have indicated that low-grade secondary inflammation involving phagocytosing macrophages amplifies demyelination, Schwann cell dedifferentiation, and perturbation of axons. The recruitment and pathogenic activation of detrimental macrophages is regulated by CSF-1, a cytokine that is mostly expressed by fibroblasts in the diseased nerve and exists in three isoforms. We show that the cell-surface and secreted isoforms of CSF-1 have opposing effects on macrophage activation and disease progression in a mouse model of CMT1X. These insights into opposing functions of disease-modulating cytokine isoforms might enable the development of specific therapeutic approaches.
authors: Department of Neurology, Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany, and groh_j@ukw.de rudolf.martini@mail.uni-wuerzburg.de.
authors: Janos
authors: J
authors: Groh
authors: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors: Ranu
authors: R
authors: Basu
authors: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors: E Richard
authors: http://orcid.org/0000-0002-2910-2065
authors: ER
authors: Stanley
authors: Department of Neurology, Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany, and groh_j@ukw.de rudolf.martini@mail.uni-wuerzburg.de.
authors: Rudolf
authors: R
authors: Martini
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism; D017630:Connexins / Q000235:genetics* / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D018628:Gene Dosage; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism*; D008264:Macrophages / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D016173:Macrophage Colony-Stimulating Factor; D008565:Membrane Proteins; D000097002:Gap Junction beta-1 Protein
keywords: CMT1X; colony stimulating factor-1; demyelination; macrophage