The Journal of Neuroscience, August 15, 1998, 18(16):6218-6229
Tenascin-R Is Antiadhesive for Activated Microglia that Induce
Downregulation of the Protein after Peripheral Nerve Injury: a New Role
in Neuronal Protection
Doychin N.
Angelov1,
Michael
Walther1,
Michael
Streppel2,
Orlando
Guntinas-Lichius2,
Wolfram F.
Neiss1,
Rainer
Probstmeier4, and
Penka
Pesheva3
Departments of 1 Anatomy and
2 Oto-Rhino-Laryngology, University of Cologne, 50924 Cologne, Germany, and Departments of 3 Physiology,
Neurophysiology, and 4 Biochemistry, Institute of Animal
Anatomy and Physiology, University of Bonn, 53111 Bonn, Germany
Microglial activation in response to pathological stimuli is
characterized by increased migratory activity and potential cytotoxic action on injured neurons during later stages of neurodegeneration. The
initial molecular changes in the CNS favoring neuronofugal migration of
microglia remain, however, largely unknown. We report that the
extracellular matrix protein tenascin-R (TN-R) present in the intact
CNS is antiadhesive for activated microglia, and its downregulation
after facial nerve axotomy may account for the loss of motoneuron
protection and subsequent neurodegeneration. Studies on the protein
expression in the facial and hypoglossal nucleus in rats demonstrate
that TN-R is a constituent of the perineuronal net of motoneurons and
7 d after peripheral nerve injury becomes downregulated in the
corresponding motor nucleus. This downregulation is reversible under
regenerative (nerve suture) conditions and irreversible under
degenerative (nerve resection) conditions. In short-term adhesion
assays, the unlesioned side of brainstem cryosections from unilaterally
operated animals is nonpermissive for activated microglia, and this
nonpermissiveness is almost abolished by a monoclonal antibody to TN-R.
Microglia-conditioned media and tumor necrosis factor-
downregulate
TN-R protein and mRNA synthesis by cultured oligodendrocytes, which are
one of the sources for TN-R in the brainstem. Our findings suggest a new role for TN-R in neuronal protection against activated microglia and the participation of the latter in perineuronal net destruction, e.g., downregulation of TN-R.
Key words:
axotomy; antiadhesive substrate; cell adhesion; extracellular matrix; facial nerve; hypoglossal nerve; microglia; oligodendrocyte; tenascin-R; TNF-
Copyright © 1998 Society for Neuroscience 0270-6474/98/18166218-12$05.00/0
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