title: Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle.
abstract: A deficiency of the dysferlin protein results in limb girdle muscular dystrophy type 2B and Miyoshi myopathy, with resulting plasma membrane abnormalities in myofibers. Many patients show muscle inflammation, but the molecular mechanisms that initiate and perpetuate this inflammation are not well understood. We previously showed abnormal activation of macrophages and hypothesized that activation of the inflammasome pathway may play a role in disease progression. To test this, we studied the inflammasome molecular platform in dysferlin-deficient human and mouse muscle. Consistent with our model, components of the NACHT, LRR and PYD-containing proteins (NALP)-3 inflammasome pathway were specifically up-regulated and activated in dysferlin-deficient but not in dystrophin-deficient and normal muscle. We demonstrate for the first time that normal primary skeletal muscle cells are capable of secreting IL-1beta in response to combined treatment with lipopolysaccharide and the P2X7 receptor agonist, benzylated ATP, suggesting that not only immune cells but also muscle cells can actively participate in inflammasome formation. In addition, we show that dysferlin-deficient primary muscle cells express toll-like receptors (TLRs; TLR-2 and TLR-4) and can efficiently produce IL-1beta in response to lipopolysaccharide and benzylated ATP. These data indicate that skeletal muscle is an active contributor of IL-1beta and strategies that interfere with this pathway may be therapeutically useful for patients with limb girdle muscular dystrophy type 2B.
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Rawat
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Cohen
authors.forename: Beryl
authors.initials: B
authors.lastname: Ampong
authors.forename: Dwight
authors.initials: D
authors.lastname: Francia
authors.forename: Andrea
authors.initials: A
authors.lastname: Henriques-Pons
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000494:pharmacology; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D000073939:Dysferlin; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009124:Muscle Proteins; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000255:Adenosine Triphosphate