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

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.