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.
Hao
Hai Peng
HP
Laboratory of Oral Aging Science, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan.
Doh-Ura
Katsumi
K
Nakanishi
Hiroshi
H
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D019771:Axotomy; D002401:Cathepsin B / Q000378:metabolism; D002403:Cathepsins / Q000172:deficiency / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D055316:Cystatin C; D015891:Cystatins / Q000378:metabolism; D015536:Down-Regulation; D005154:Facial Nerve / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009000:Monocytes / Q000166:cytology; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology; D019063:Tenascin / Q000378:metabolism; D014018:Tissue Distribution
C525031:Cst3 protein, mouse; D055316:Cystatin C; D015891:Cystatins; D000949:Histocompatibility Antigens Class II; D019063:Tenascin; C074638:tenascin R; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000255:Adenosine Triphosphate; D002403:Cathepsins; D002401:Cathepsin B; C028217:cathepsin S