title: Bcl-2 inhibits the innate immune response during early pathogenesis of murine congenital muscular dystrophy.
abstract: Laminin α2 (LAMA2)-deficient congenital muscular dystrophy is a severe, early-onset disease caused by abnormal levels of laminin 211 in the basal lamina leading to muscle weakness, transient inflammation, muscle degeneration and impaired mobility. In a Lama2-deficient mouse model for this disease, animal survival is improved by muscle-specific expression of the apoptosis inhibitor Bcl-2, conferred by a MyoD-hBcl-2 transgene. Here we investigated early disease stages in this model to determine initial pathological events and effects of Bcl-2 on their progression. Using quantitative immunohistological and mRNA analyses we show that inflammation occurs very early in Lama2-deficient muscle, some aspects of which are reduced or delayed by the MyoD-hBcl-2 transgene. mRNAs for innate immune response regulators, including multiple Toll-like receptors (TLRs) and the inflammasome component NLRP3, are elevated in diseased muscle compared with age-matched controls expressing Lama2. MyoD-hBcl-2 inhibits induction of TLR4, TLR6, TLR7, TLR8 and TLR9 in Lama2-deficient muscle compared with non-transgenic controls, and leads to reduced infiltration of eosinophils, which are key death effector cells. This congenital disease model provides a new paradigm for investigating cell death mechanisms during early stages of pathogenesis, demonstrating that interactions exist between Bcl-2, a multifunctional regulator of cell survival, and the innate immune response.
authors.affiliation: Boston Biomedical Research Institute, Watertown, Massachusetts, United States of America.
authors.forename: Sheila
authors.initials: S
authors.lastname: Jeudy
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Wardrop
authors.forename: Amy
authors.initials: A
authors.lastname: Alessi
authors.forename: Janice A
authors.initials: JA
authors.lastname: Dominov
mesh_terms: D000818:Animals; D015153:Blotting, Western; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D017254:Leukemic Infiltration / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; C552579:TLR8 protein, mouse; C493487:Tlr4 protein, mouse; C495369:Tlr6 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9