The role of TRAIL in mediating autophagy in myositis skeletal muscle: A potential nonimmune mechanism of muscle damage

Objective Multinucleated cells are relatively resistant to classic apoptosis, and the factors initiating cell death and damage in myositis are not well defined. We hypothesized that nonimmune autophagic cell death may play a role in muscle fiber damage. Recent reports indicate that TRAIL may induce both NF-IκB activation and autophagic cell death in other systems. We undertook this study to investigate the role of TRAIL in cell death and pathogenesis in vitro and in vivo, using myositis muscle tissues from humans and mice. Methods Gene expression profiling was performed in myositis patient and control muscle specimens. Immunohistochemistry analysis was performed to confirm the gene array findings. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NF-IκB activation in vitro in cultured cells. Results TRAIL was expressed predominantly in myositis muscle fibers, but not in biopsy specimens from normal or other dystrophic-diseased muscle. Autophagy markers were up-regulated in humans with myositis and in mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NF-IκB activation and IIκB degradation in cultured cells that are resistant to TRAIL-induced apoptosis but that undergo autophagic cell death. Conclusion Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NF-IκB and autophagic cell death in myositis. Thus, this nonimmune pathway may be an attractive target for therapeutic intervention in myositis.