Immune-mediated mechanisms potentially regulate the disease time-course of duchenne muscular dystrophy and provide targets for therapeutic intervention

Abstract

Duchenne muscular dystrophy is a lethal muscle-wasting disease that affects boys. Mutations in the dystrophin gene result in the absence of the dystrophin glycoprotein complex (DGC) from muscle plasma membranes. In healthy muscle fibers, the DGC forms a link between the extracellular matrix and the cytoskeleton to protect against contraction-induced membrane lesions and to regulate cell signaling. The absence of the DGC results in aberrant regulation of inflammatory signaling cascades. Inflammation is a key pathological characteristic of dystrophic muscle lesion formation. However, the role and regulation of this process in the disease time-course has not been sufficiently examined. The transcription factor nuclear factor-kappaB has been shown to contribute to the disease process and is likely involved with increased inflammatory gene expression, including cytokines and chemokines, found in dystrophic muscle. These aberrant signaling processes may regulate the early time-course of inflammatory events that contribute to the onset of disease. This review critically evaluates the possibility that dystrophic muscle lesions in both patients with Duchenne muscular dystrophy and mdx mice are the result of immune-mediated mechanisms that are regulated by inflammatory signaling and also highlights new therapeutic directions.

Figure 1

The dystrophin glycoprotein complex (DGC) in normal myofibers. Illustration of the link formed between laminin in the extracellular matrix (ECM) and the cytoskeleton by the DGC. Also shown, interaction of DGC components (dystrophin, dystroglycans, dystrobrevin, laminin, sarcoglycans, syntrophin, and sarcospan) with potential signaling proteins (Grb2, SOS, RAS, NOS, CaM, CaMKII), and with stretch activated channels (SAC) through which calcium (Ca) can enter the cell. Reprinted with permission. Evans NP, Misyak SA, Robertson JL, Bassaganya-Riera J, Grange RW. Dysregulated intracellular signaling and inflammatory gene expression during initial disease onset in Duchenne muscular dystrophy. Am J Phys Med Rehabil 2009;88:502-522.

Figure 2

Possible immune cell interactions in dystrophic muscle. Macrophages, CD4+, and CD8+ cells appear to primarily interact within the muscle tissue of mdx mice, whereas in a typical immune response, APC's would engulf antigens and carry them back to draining lymph nodes to interact with CD4+ and CD8+ T cells. Dystrophic muscle fibers likely produce antigens which are engulfed by macrophages and are activated by additional inflammatory stimuli. In DMD patients, T cells have specific TCR rearrangements that may allow them to interact with APC which express MHC I and II. Therefore, one possibility is that macrophages (which have both MHC I and II proteins on their surface) could induce muscle fiber death through nitric oxide mediated cell lysis or present antigen, bound to MHC II, to CD4+ T cells through their T cell receptors. Activated CD4+ T cells would then produce cytokines to activate CD8+ T cells. When receptors on CD8+ T cells come in contact with antigen, they bind to MHC I on the surface of muscle fibers and could induce muscle fiber death.

Figure 3

Possible pathways resulting inNF-κB activation. (A) In WT muscle fibers the DGC may play key role in regulating or suppressing NF-κB activation but the mechanism for how this happens has not been defined. (B) In mdx muscle fibers, the loss of the DGC has been reported to contribute to changes in signaling pathways that increase NF-κB activation. Reprinted with permission. Evans NP, Misyak SA, Robertson JL, Bassaganya-Riera J, Grange RW. Dysregulated intracellular signaling and inflammatory gene expression during initial disease onset in Duchenne muscular dystrophy. Am J Phys Med Rehabil 2009;88:502-522.

Figure 3

Possible pathways resulting inNF-κB activation. (A) In WT muscle fibers the DGC may play key role in regulating or suppressing NF-κB activation but the mechanism for how this happens has not been defined. (B) In mdx muscle fibers, the loss of the DGC has been reported to contribute to changes in signaling pathways that increase NF-κB activation. Reprinted with permission. Evans NP, Misyak SA, Robertson JL, Bassaganya-Riera J, Grange RW. Dysregulated intracellular signaling and inflammatory gene expression during initial disease onset in Duchenne muscular dystrophy. Am J Phys Med Rehabil 2009;88:502-522.

Figure 4

Possible interactions of extracellular immune signaling pathways in dystrophic muscle. In DMD and mdx (M) muscle tissue, elevated levels of (C) chemokines and (P) pro-inflammatory cytokines are produced, which when released into the ECM can act as chemoattractants for a variety of (I) immune cells. Although the process has not been described in dystrophic muscle, activated immune cells may travel to sites of muscle damage where they can release pro-inflammatory and (A) anti-inflammatory cytokines. The balance between pro-inflammatory and anti-inflammatory cytokines may regulate the level of immune cell activation in dystrophic muscle and resulting muscle fiber death.