title: PKC theta ablation improves healing in a mouse model of muscular dystrophy.
abstract: Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, limiting muscle regeneration and resulting in fibrotic and fatty tissue replacement of muscle, which exacerbates the wasting process in dystrophic muscles. Limiting immune response is thus one of the therapeutic options to improve healing, as well as to improve the efficacy of gene- or cell-mediated strategies to restore dystrophin expression. Protein kinase C θ (PKCθ) is a member of the PKCs family highly expressed in both immune cells and skeletal muscle; given its crucial role in adaptive, but also innate, immunity, it is being proposed as a valuable pharmacological target for immune disorders. In our study we asked whether targeting PKCθ could represent a valuable approach to efficiently prevent inflammatory response and disease progression in a mouse model of muscular dystrophy. We generated the bi-genetic mouse model mdx/θ(-/-), where PKCθ expression is lacking in mdx mice, the mouse model of Duchenne muscular dystrophy. We found that muscle wasting in mdx/θ(-/-) mice was greatly prevented, while muscle regeneration, maintenance and performance was significantly improved, as compared to mdx mice. This phenotype was associated to reduction in inflammatory infiltrate, pro-inflammatory gene expression and pro-fibrotic markers activity, as compared to mdx mice. Moreover, BM transplantation experiments demonstrated that the phenotype observed was primarily dependent on lack of PKCθ expression in hematopoietic cells.These results demonstrate a hitherto unrecognized role of immune-cell intrinsic PKCθ activity in the development of DMD. Although the immune cell population(s) involved remain unidentified, our findings reveal that PKCθ can be proposed as a new pharmacological target to counteract the disease, as well as to improve the efficacy of gene- or cell- therapy approaches.
authors.affiliation: Unit of Histology, and IIM, Sapienza University, DAHFMO, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Madaro
authors.forename: Andrea
authors.initials: A
authors.lastname: Pelle
authors.forename: Carmine
authors.initials: C
authors.lastname: Nicoletti
authors.forename: Annunziata
authors.initials: A
authors.lastname: Crupi
authors.forename: Valeria
authors.initials: V
authors.lastname: Marrocco
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bossi
authors.forename: Silvia
authors.initials: S
authors.lastname: Soddu
authors.forename: Marina
authors.initials: M
authors.lastname: Bouché
mesh_terms: D000818:Animals; D005355:Fibrosis; D007167:Immunotherapy / Q000379:methods; D007249:Inflammation / Q000517:prevention & control; D007527:Isoenzymes / Q000172:deficiency*; D051379:Mice; D009137:Muscular Dystrophy, Animal / Q000473:pathology / Q000628:therapy*; D011493:Protein Kinase C / Q000172:deficiency*; D000074121:Protein Kinase C-theta; D016896:Treatment Outcome; D019282:Wasting Syndrome
chemical_list: D007527:Isoenzymes; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta