Role of Thrombospondin 1 in Macrophage Inflammation in Dysferlin Myopathy
Por:
De Luna, N, Gallardo, E, Sonnet, C, Chazaud, B, Dominguez-Perles, R, Suarez-Calvet, X, Gherardi, RK, Illa, I
Publicada:
1 jun 2010
Resumen:
Muscle inflammation can be a prominent feature in several muscular dystrophies. In dysferlin myopathy, it is mainly composed of macrophages. To understand the origin of inflammation in dysferlin-deficient muscle, we analyzed soluble factors involved in monocyte chemotaxis released by myoblasts and myotubes from control and dysferlinopathy patients using a transwell system. Dysferlin-deficient myotubes released more soluble factors involved in monocyte chemotaxis compared with controls (p < 0.001). Messenger RNA microarray analysis showed a 3.2-fold increase of thrombospondin 1 (TSP-1) expression in dysferlin-deficient myotubes. Retrotranscriptase polymerase chain reaction analysis, ELISA, and immunohistochemistry confirmed these results. Dysferlin mRNA knockdown with short-interfering RNA in normal myogenic cells resulted in TSP-1 mRNA upregulation and increased chemotaxis. Furthermore, monocyte chemotaxis was decreased when TSP-1 was blocked by specific antibodies. In muscle biopsies from dysferlinopathy patients, TSP-1 expression was increased in muscle fibers but not in biopsies of patients with other myopathies with inflammation; TSP-1 was seen in some macrophages in all samples analyzed. Taken together, the data demonstrate that dysferlin-deficient muscle upregulates TSP-1 in vivo and in vitro and indicate that endogenous chemotactic factors are crucial to the sustained inflammatory process observed in dysferlinopathies.
Filiaciones:
De Luna, N:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Lab Neurol Expt, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Gallardo, E:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Lab Neurol Expt, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Sonnet, C:
Univ Paris 12, INSERM, U955 E10, F-94000 Creteil, France
Chazaud, B:
Univ Paris 12, INSERM, U955 E10, F-94000 Creteil, France
Dominguez-Perles, R:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Lab Neurol Expt, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Suarez-Calvet, X:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Lab Neurol Expt, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Gherardi, RK:
Univ Paris 12, INSERM, U955 E10, F-94000 Creteil, France
Illa, I:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Serv Neurol, Barcelona 08025, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Lab Neurol Expt, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Bronze
|