Department of Nutritional Physiology, Institute of Health Biosciences, University of Tokushima, Tokushima, Japan.
Muscle Nerve. 2011 Feb;43(2):223-9. doi: 10.1002/mus.21829. Epub 2010 Nov 16.
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.
Cbl-b 泛素连接酶基因缺失会激活小鼠巨噬细胞。本研究旨在阐明 Cbl-b 缺陷型小鼠肌肉退行性/再生过程中巨噬细胞的病理生理作用。我们检测了 Cbl-b 缺陷型小鼠经肌肉注射心肌毒素后，其肌内的免疫细胞浸润和细胞因子表达情况。与野生型小鼠相比，Cbl-b 基因缺失会延迟心肌毒素诱导的骨骼肌损伤的再生。在 Cbl-b 缺陷型小鼠，心肌毒素注射后 14 天，受损肌肉内仍存在 CD8 阳性 T 细胞，但在野生型小鼠中，这些细胞在这段时间内分散开来。Cbl-b 缺陷型小鼠浸润的巨噬细胞强烈表达 RANTES（激活调节正常 T 细胞表达和分泌），这是一种趋化因子，可趋化 CD8 阳性 T 细胞。相反，抗 RANTES 的中和抗体可显著抑制 CD8 阳性 T 细胞浸润肌肉，从而恢复紊乱的肌肉再生。Cbl-b 通过巨噬细胞中 RANTES 的产生，是细胞毒性 T 细胞浸润的重要调节因子。
