The Role of Macrophages in Demyelinating Peripheral Nervous System of Mice Heterozygously Deficient in P0

Carenini, Stefano; Mäurer, Mathias; Werner, Alexander; Blazyca, Heinrich; Toyka, Klaus V.; Schmid, Christoph D.; Raivich, Gennadij; Martini, Rudolf

doi:10.1083/jcb.152.2.301

Cited by 115 publications

(129 citation statements)

References 53 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, macrophages in the TrJ nerve maintain a close spatial relationship with myelinated nerve axons. Though it is known that macrophages contribute to peripheral nerve demyelination in both P0 and connexin-32 peripheral neuropathies (Schmid et al 2000;Carenini et al 2001;Kobsar et al 2002), and likely do so in the TrJ neuropathy, it is not fully clear if MMPs directly participate in myelin degradation (Leppert et al 1999). Nonetheless, both MMP-2 and MMP-9 may degrade myelin basic protein, a prominent constituent of peripheral nerve myelin (Chandler et al 1995), and an undetermined MMP activity degrades P0 (Cammer et al 1981).…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves

Misko

Ferguson

Notterpek

2002

Journal of Neurochemistry

View full text Add to dashboard Cite

A single point mutation in peripheral myelin protein 22 (pmp22) of the Trembler-J (TrJ) mouse models the human peripheral neuropathy, Charcot-Marie-Tooth disease type 1 A (CMT1A). An unexplored aspect of this disease is the gradual remodeling of the extracellular matrix in affected nerves. To elucidate the mechanism responsible for these changes, the levels of the extracellular matrix molecules laminin, collagen IV, and fibronectin were determined. In TrJ nerves, laminin is modestly increased while full-length forms of collagen IV and fibronectin are decreased. Matrix metalloproteinases (MMPs) are known to degrade multiple matrix molecules; therefore, nerves were assayed for MMP-2 and MMP-9 proteins. In neuropathy nerves, elevated levels of MMP-2 and MMP-9 were detected on western blots, and gelatin zymography confirmed the up-regulation of gelatinalytic activity in affected samples. Immunostaining studies revealed an increase in the numbers of MMP-2-and MMP-9-expressing cells in TrJ nerves. Cell type-specific immunolabeling showed that infiltrating macrophages are a significant source of both MMP-2 and MMP-9. Finally, the degradation of exogenous collagen IV by TrJ nerve lysates was prevented with a specific MMP inhibitor. Together these observations suggest that infiltration by MMP-expressing macrophages contributes to the remodeling of the TrJ nerve matrix.

show abstract

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves

Misko

Ferguson

Notterpek

2002

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Figure 2 summarizes the cellular elements, molecules and the pathways involved in genetically mediated demyelination in mouse mutants in the corresponding temporal context. Whereas CD8 1 T cells are numerically elevated relatively late in the mutant peripheral nerve at approximately 6 months of age, macrophages are the first cells to be found in increased cell numbers in affected nerves of myelin mutants from postnatal month 3 onwards (Carenini et al, 2001;Kobsar et al, 2002;Schmid et al, 2000). It is, therefore, plausible to assume that specific signals originating from the mutant Schwann cells of the peripheral nerves may mediate macrophage influx and proliferation.…”

Section: Macrophages Increase In Number and Associate With Myelin In mentioning

confidence: 99%

“…There is a subtle, but significant difference between the myelin-macrophage interactions in the demyelinating mutants. In P0 1/2 mice and in mice over-expressing PMP22, well-preserved myelin in direct contact with macrophages is often seen (Carenini et al, 2001;Kobsar et al, 2005), suggesting that the macrophages phagocytose normal appearing myelin. In contrast, in Cx32 2/2 mutants, myelin sheaths in direct contact with endoneurial tube macrophages are rarely seen and, if detected, the myelin always appears damaged or vacuolized and could never be found in an ultrastructurally ''intact'' state (Kobsar et al, 2002).…”

Section: Macrophages Increase In Number and Associate With Myelin In mentioning

confidence: 99%

Interactions between Schwann cells and macrophages in injury and inherited demyelinating disease

Martini

Fischer

López-Vales

et al. 2008

Glia

Self Cite

278

239

View full text Add to dashboard Cite

In this article we first discuss the factors that regulate macrophage recruitment, activation, and myelin phagocytosis during Wallerian degeneration and some of the factors involved in the termination of inflammation at the end of the period of Wallerian degeneration after peripheral nerve injuries. In particular, we deal with the early events that trigger chemokine and cytokine expression; the role of phospholipase A 2 in initiating the breakdown of compact myelin, and chemokine, cytokine expression; and the role of MCP-1, MIP-1a, and IL-1b in macrophage recruitment and myelin phagocytosis. We also discuss how inflammation may be switched off and the recently identified role of the Nogo receptor on activated macrophages in the clearance of these cells from the injured nerve. In the second half of the article we focus on the role of certain Schwann cell borne cytokines and chemokines, such as M-CSF and MCP-1 as well as intracellular signaling that regulate their expression in animal models of inherited demyelinating disease. Additionally, we present the preservation of sensory nerves fibers from macrophage attack in these animal models as a challenging paradigm for the development of putative treatment approaches. Finally, we also discuss the similarities and differences in these Schwann cell-macrophage responses in injury-induced Wallerian degeneration and inherited demyelinating diseases. Knowledge of the molecular mechanisms underlying Schwann cell-macrophage interaction under pathological conditions is an important prerequisite to develop effective treatment strategies for various peripheral nerve disorders. V V C

show abstract

“…Plantar and median nerves were carefully removed under a dissection microscope at the level of the ankle joint and wrist, respectively, and postfixed in the same fixative. Tissue preparation (osmification, dehydration, and embedding in Spurr) for electron microscopy was performed as described previously (Carenini et al, 2001). The number of myelinated axons was counted in ultrathin sections.…”

Section: Methodsmentioning

confidence: 99%

Triple Knock-Out ofCNTF,LIF, andCT-1Defines Cooperative and Distinct Roles of these Neurotrophic Factors for Motoneuron Maintenance and Function

Holtmann¹,

Wiese²,

Samsam³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

Members of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor (LIF) gene family play an essential role for survival of developing and postnatal motoneurons. When subunits of the shared receptor complex are inactivated by homologous recombination, the mice die at approximately birth and exhibit reduced numbers of motoneurons in the spinal cord and brainstem nuclei. However, mice in which cntf, lif, or cardiotrophin-1 (ct-1) are inactivated can survive and show less motoneuron cell loss. This suggests cooperative and redundant roles of these ligands. However, their cooperative functions are not well understood. We generated cntf/lif/ct-1 triple-knockout and combinations of double-knock-out mice to study the individual and combined roles of CNTF, LIF and CT-1 on postnatal motoneuron survival and function. Triple-knock-out mice exhibit increased motoneuron cell loss in the lumbar spinal cord that correlates with muscle weakness during early postnatal development. LIF deficiency leads to pronounced loss of distal axons and motor endplate alterations, whereas CNTF-and/or CT-1-deficient mice do not show significant changes in morphology of these structures. In cntf/lif/ct-1 triple-knock-out mice, various degrees of muscle fiber type grouping are found, indicating that denervation and reinnervation had occurred. We conclude from these findings that CNTF, LIF, and CT-1 have distinct functions for motoneuron survival and function and that LIF plays a more important role for postnatal maintenance of distal axons and motor endplates than CNTF or CT-1.

show abstract

The Role of Macrophages in Demyelinating Peripheral Nervous System of Mice Heterozygously Deficient in P0

Cited by 115 publications

References 53 publications

Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves

Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves

Interactions between Schwann cells and macrophages in injury and inherited demyelinating disease

Triple Knock-Out ofCNTF,LIF, andCT-1Defines Cooperative and Distinct Roles of these Neurotrophic Factors for Motoneuron Maintenance and Function

Contact Info

Product

Resources

About