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Third-party-funded project

Molecular mechanisms of the differential activation of microglia and macrophages in nerve injury and their role in nerve regeneration

Project management at the University of Würzburg:

Participating scientists:

Lesioning a nerve or fibre tract leads to degeneration of the distal segment, a process named Wallerian degeneration (WD). In the peripheral nervous system (PNS) nerve fibres from the proximal nerve stump promptly grow into the distal degenerating stump, a regenerative response that is lacking in the central nervous system (CNS). Although the molecular mechanisms underlying these different regenerative responses are largely unknown, there is evidence that the distal stump of an injured PNS nerve contains a specific molecular milieu that involves macrophage invasion (Stoll & Jander, 1999; Stoll & Müller, 1999). We have recently shown that macrophages are specifically differentiated and express CD8 in peripheral nerve injury (Jander et al., 2001), and that axonal injury can induce expression of the proinflammatory cytokine IL-18 in infiltrating macrophages (Menge et al., 2001). Surprisingly, peripheral nerve infiltrating macrophages lack expression of the scar-forming protein osteopontin in contrast to optic nerve and spinal cord lesions (Jander et al., 2002). These findings point to lesionspecific macrophage phenotypes, the functional contribution of which to regeneration are currently under investigation. In CNS fibre tract injury macrophage recruitment is restricted to the lesion site, while microglia in the distal stumps are activated, but do not transform into phagocytes as in cerebral ischemia leading to persistence of growth inhibitory myelin debris (Stoll & Jander, 1999). We could show that this is not due to lack of proinflammatory cytokines (Menge et al., 2001), but rather reflects the presence of a local inhibitory factor for phagocytic transformation. We are currently investigating means to manipulate the microglial response in order to facilitate regeneration.

Key words:
    nerve regeneration
    molecular biology

Projekt period: from 10.1999 to 09.2002

Funding institution:
DFG ,Granting date: 30.09.1999