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Impairment of microglial responses to facial nerve axotomy in cathepsin S–deficient mice

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Abstract

Cathepsin S (CS) is a lysosomal/endosomal cysteine protease especially expressed in cells of a mononuclear lineage including microglia. To better understand the role of CS in microglia, we investigated microglial responses after a facial nerve axotomy in CS-deficient (CS−/−) and wild-type mice. Microglia in both groups accumulated in the facial motor nucleus following axotomy. However, the mean number of microglia in CS−/− mice on the axotomized side was significantly smaller than that in wild-type mice. Microglia were found to adhere to injured motoneurons in wild-type mice, whereas microglia abutted on injured motoneurons without spreading on their surface in CS−/− mice. At the same time, the axotomy-induced down-regulation of tenasin-R, an antiadhesive perineuronal net for microglia, was partially abrogated in CS−/− mice. Primary cultured microglia prepared from CS−/− mice showed that CS deficiency caused significant suppression of migration and transmigration of microglia. In CS−/− mice, impaired recruitments of circulating monocytes and T lymphocytes and reduced expression of the class II major compatibility complex on the axotomized side were observed. Interestingly, cathepsin B, a typical lysosomal cysteine protease, was markedly expressed on the axotomized side in CS−/− but not in wild-type microglia. Finally, we compared axotomy-induced neuronal death in the two groups and found that the percentage of motoneurons that survived in CS−/− mice was significantly smaller than that in wild-type mice. The present study strongly suggests that CS plays a role in the migration and activation of microglia to protect facial motoneurons against axotomy-induced injury. © 2007 Wiley-Liss, Inc.

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