Cell-surface and secreted isoforms of csf-1 exert opposing roles in macrophage-mediated neural damage in Cx32-deficient mice

Janos Groh, Ranu Basu, E. Richard Stanley, Rudolf Martini

Research output: Contribution to journalArticle

5 Citations (Scopus)

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. Hereweinvestigated the impact of cell-surface and secreted isoforms of CSF-1 on macrophagerelated 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 dosedependently. 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.

Original languageEnglish (US)
Pages (from-to)1890-1901
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number6
DOIs
StatePublished - Feb 10 2016

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Macrophage Colony-Stimulating Factor
Protein Isoforms
Macrophages
Macrophage Activation
Fibroblasts
Cell Dedifferentiation
Genetic Hybridization
Inflammation
Schwann Cells
Demyelinating Diseases
Proteoglycans
Myelin Sheath
Peripheral Nerves
Phagocytosis
Axons
Tooth
Cell Membrane
Cytokines
Biopsy

Keywords

  • CMT1X
  • Colony stimulating factor-1
  • Demyelination
  • Macrophage

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Cell-surface and secreted isoforms of csf-1 exert opposing roles in macrophage-mediated neural damage in Cx32-deficient mice. / Groh, Janos; Basu, Ranu; Stanley, E. Richard; Martini, Rudolf.

In: Journal of Neuroscience, Vol. 36, No. 6, 10.02.2016, p. 1890-1901.

Research output: Contribution to journalArticle

Groh, Janos ; Basu, Ranu ; Stanley, E. Richard ; Martini, Rudolf. / Cell-surface and secreted isoforms of csf-1 exert opposing roles in macrophage-mediated neural damage in Cx32-deficient mice. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 6. pp. 1890-1901.
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