Rantes secreted from macrophages disturbs skeletal muscle regeneration after cardiotoxin injection in Cbl-b-deficient mice.
Deficiency of the Cbl-b ubiquitin ligase gene activates macrophages in mice. This study aimed to elucidate the pathophysiological roles of macrophages in muscle degeneration/regeneration in Cbl-b-deficient mice. We examined immune cell infiltration and cytokine expression in cardiotoxin-injected tibialis anterior muscle of Cbl-b-deficient mice. Ablation of the Cbl-b gene expression delayed regeneration of cardiotoxin-induced skeletal muscle damage compared with wild-type mice. CD8-positive T cells were still present in the damaged muscle on day 14 after cardiotoxin injection in Cbl-b-deficient mice, but there was dispersal of the same cells over that time-frame in wild-type mice. Infiltrating macrophages in Cbl-b-deficient mice showed strong expression of RANTES (regulated-on-activation, normal T cell expressed and secreted), a chemokine for CD8-positive T cells. In turn, a neutralizing antibody against RANTES significantly suppressed the infiltration of CD8-positive T cells into the muscle, resulting in restoration of the disturbed muscle regeneration. Cbl-b is an important regulatory factor for cytotoxic T-cell infiltration via RANTES production in macrophages.
Department of Nutritional Physiology, Institute of Health Biosciences, University of Tokushima, Tokushima, Japan.
Shohei
S
Kohno
Tatsuya
T
Ueji
Tomoki
T
Abe
Reiko
R
Nakao
Katsuya
K
Hirasaka
Motoko
M
Oarada
Akiko
A
Harada-Sukeno
Ayako
A
Ohno
Akira
A
Higashibata
Rie
R
Mukai
Junji
J
Terao
Yuushi
Y
Okumura
Takeshi
T
Nikawa
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D054715:Cardiotoxins / Q000494:pharmacology*; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D018006:Myogenic Regulatory Factors; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency*; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D015703:Antigens, CD; D054715:Cardiotoxins; C118387:Cblb protein, mouse; D018946:Chemokine CCL5; D016207:Cytokines; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; C063403:myogenic factor 6; D050721:Proto-Oncogene Proteins c-cbl