The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy.
Oxidative stress and nuclear factor-kappaB (NF-kappaB) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N(epsilon)-carboxymethyllysine (CML) results in the activation of NF-kappaB and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-kappaB in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-kappaB were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-kappaB and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-kappaB was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-kappaB in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-kappaB were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-kappaB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-kappaB activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD.
Haslbeck
K M
KM
Department of Neurology, University Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany, matthias.haslbeck@neuro.imed.uni-erlangen.de
Friess
U
U
Schleicher
E D
ED
Bierhaus
A
A
Nawroth
P P
PP
Kirchner
A
A
Pauli
E
E
Neundörfer
B
B
Heuss
D
D
D000328:Adult; D000368:Aged; D003882:Dermatomyositis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D017127:Glycation End Products, Advanced; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D009220:Myositis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D017285:Polymyositis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000502:physiology
D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C048496:N(6)-carboxymethyllysine; D008239:Lysine