Duchenne muscular dystrophy (DMD) is a lethal X-linked disease characterized by progressive muscle degeneration and chronic inflammation. RAGE (Receptor for Advanced Glycation End-products) is a multiligand receptor of immunoglobulin superfamily involved in inflammation and myogenesis.1 RAGE is absent in healthy adult muscle tissue but it is expressed in regenerating myofibers, dystrophic muscles and activated immune cells.2,3 The double mutant mdx/Ager–/– mice, lacking dystrophin and RAGE, show significantly reduced numbers of necrotic myofibers, a shift towards higher values of cross-sectional areas (CSA) of regenerating myofibers, and reduced recruitment of activated macrophages (MΦ) in muscle tissue, compared with mdx mice. Interestingly, the MΦ (F4/80+/CD11b+) population found in muscles of 5 week-old mdx/Ager–/– mice was mostly composed by anti-inflammatory M2a (CD163-/Cd206+) and regenerative M2c (CD163+/Cd206+) MΦ, and showed dramatic reduction in M1 pro-inflammatory MΦ in comparison with age-matched mdx mice, as assessed by FACS analysis. Moreover, peritoneal MΦ from Ager–/– mice express lower levels of TNFα, IFNγ, IL-6, IL-12a and IL-12b compared with WT mice, when stimulated with the pro-inflammatory factors, LPS/IFNγ in vitro. Our results suggest that RAGE expressed on MΦ has a major role in sustaining the inflammatory process in dystrophic muscles. Thus, the inhibition of RAGE expression/activity in muscles of DMD patients might represent a therapeutic tool to reduce inflammation and rescue muscle morphology. *Contributed equally to this work. 1. Sorci G, et al. Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol Cell Biol 2004;24:4880. 2. Riuzzi F, et al. HMGB1–RAGE regulates muscle satellite cell homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 transcription. J Cell Sci 2012;125:1440-54. 3. Haslbeck KM, et al. The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy. Acta Neuropathol 2005;110:247-254.
The novel DMD experimental model, mdx/Ager–/– mouse reveals a role of RAGE in inflammatory processes in dystrophic muscles.
SALVADORI, LAURA;CHIAPPALUPI, SARA;RIUZZI, Francesca;SORCINI, DANIELE;RICCARDI, Carlo;DONATO, Rosario Francesco;SORCI, Guglielmo
2017
Abstract
Duchenne muscular dystrophy (DMD) is a lethal X-linked disease characterized by progressive muscle degeneration and chronic inflammation. RAGE (Receptor for Advanced Glycation End-products) is a multiligand receptor of immunoglobulin superfamily involved in inflammation and myogenesis.1 RAGE is absent in healthy adult muscle tissue but it is expressed in regenerating myofibers, dystrophic muscles and activated immune cells.2,3 The double mutant mdx/Ager–/– mice, lacking dystrophin and RAGE, show significantly reduced numbers of necrotic myofibers, a shift towards higher values of cross-sectional areas (CSA) of regenerating myofibers, and reduced recruitment of activated macrophages (MΦ) in muscle tissue, compared with mdx mice. Interestingly, the MΦ (F4/80+/CD11b+) population found in muscles of 5 week-old mdx/Ager–/– mice was mostly composed by anti-inflammatory M2a (CD163-/Cd206+) and regenerative M2c (CD163+/Cd206+) MΦ, and showed dramatic reduction in M1 pro-inflammatory MΦ in comparison with age-matched mdx mice, as assessed by FACS analysis. Moreover, peritoneal MΦ from Ager–/– mice express lower levels of TNFα, IFNγ, IL-6, IL-12a and IL-12b compared with WT mice, when stimulated with the pro-inflammatory factors, LPS/IFNγ in vitro. Our results suggest that RAGE expressed on MΦ has a major role in sustaining the inflammatory process in dystrophic muscles. Thus, the inhibition of RAGE expression/activity in muscles of DMD patients might represent a therapeutic tool to reduce inflammation and rescue muscle morphology. *Contributed equally to this work. 1. Sorci G, et al. Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol Cell Biol 2004;24:4880. 2. Riuzzi F, et al. HMGB1–RAGE regulates muscle satellite cell homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 transcription. J Cell Sci 2012;125:1440-54. 3. Haslbeck KM, et al. The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy. Acta Neuropathol 2005;110:247-254.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
