Journal Article

Bcl-2 Inhibits the Innate Immune Response during Early Pathogenesis of Murine Congenital Muscular Dystrophy

Wardrop, Katherine E., Alessi, Amy, Jeudy, Sheila, Dominov, Janice A.

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animal diseases / Animals / Apoptosis / Autophagy / Basal lamina / Bcl-2 protein / Biology / Biomedical research / Blotting, Western / Cell death / Cell survival / Congenital diseases / Cytokines / Degeneration / Disease / Dystrophy / Effector cells / Endoplasmic reticulum / Eosinophils / Gene expression / Genetic engineering / Heparan sulfate / Immune response / Immune system / Immunity, Innate - genetics / Immunity, Innate - immunology / In Situ Nick-End Labeling / Infiltration / Inflammasomes / Inflammation / Innate immunity / Laminin / Leukemic Infiltration - genetics / Leukemic Infiltration - immunology / Leukemic Infiltration - metabolism / Leukocytes (eosinophilic) / Ligands / Membrane Glycoproteins - genetics / Membrane Glycoproteins - metabolism / Mice / Mice, Inbred C57BL / Mice, Mutant Strains / mRNA / Muscle function / Muscles / Muscular dystrophy / Muscular Dystrophy, Animal - genetics / Muscular Dystrophy, Animal - immunology / Muscular Dystrophy, Animal - metabolism / MyoD protein / Neuromuscular diseases / Pathogenesis / Pathology / Proteins / Proto-Oncogene Proteins c-bcl-2 - genetics / Proto-Oncogene Proteins c-bcl-2 - metabolism / Receptors / Regulators / Reverse Transcriptase Polymerase Chain Reaction / RNA / Stress response / Survival / TLR4 protein / TLR7 protein / TLR9 protein / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - metabolism / Toll-Like Receptor 6 - genetics / Toll-Like Receptor 6 - metabolism / Toll-Like Receptor 7 - genetics / Toll-Like Receptor 7 - metabolism / Toll-Like Receptor 8 - genetics / Toll-Like Receptor 8 - metabolism / Toll-Like Receptor 9 - genetics / Toll-Like Receptor 9 - metabolism / Toll-like receptors