title: Toll-like receptor 4 ablation in mdx mice reveals innate immunity as a therapeutic target in Duchenne muscular dystrophy.
abstract: Toll-like receptor 4 (TLR4) recognizes specific structural motifs associated with microbial pathogens and also responds to certain endogenous host molecules associated with tissue damage. In Duchenne muscular dystrophy (DMD), inflammation plays an important role in determining the ultimate fate of dystrophic muscle fibers. In this study, we used TLR4-deficient dystrophic mdx mice to assess the role of TLR4 in the pathogenesis of DMD. TLR4 expression was increased and showed enhanced activation following agonist stimulation in mdx diaphragm muscle. Genetic ablation of TLR4 led to significantly increased muscle force generation in dystrophic diaphragm muscle, which was associated with improved histopathology including decreased fibrosis, as well as reduced pro-inflammatory gene expression and macrophage infiltration. TLR4 ablation in mdx mice also altered the phenotype of muscle macrophages by inducing a shift toward a more anti-inflammatory (iNOS(neg) CD206(pos)) profile. In vitro experiments confirmed that lack of TLR4 is sufficient to influence macrophage activation status in response to classical polarizing stimuli such as IFN-gamma and IL-4. Finally, treatment of dystrophic mice with glycyrrhizin, an inhibitor of the endogenous TLR4 ligand, high mobility group box (HMGB1), also pointed to involvement of the HMGB1-TLR4 axis in promoting dystrophic diaphragm pathology. Taken together, our findings reveal TLR4 and the innate immune system as important players in the pathophysiology of DMD. Accordingly, targeting either TLR4 or its endogenous ligands may provide a new therapeutic strategy to slow disease progression.
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre.
authors.forename: Christian
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre.
authors.forename: Kamalika
authors.initials: K
authors.lastname: Mojumdar
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre.
authors.forename: Feng
authors.initials: F
authors.lastname: Liang
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre.
authors.forename: Christian
authors.initials: C
authors.lastname: Lemaire
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre.
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pathology, McGill University and.
authors.forename: John
authors.initials: J
authors.lastname: Richardson
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre.
authors.forename: Maziar
authors.initials: M
authors.lastname: Divangahi
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre, Department of Critical Care, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Salman
authors.initials: S
authors.lastname: Qureshi
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre, basil.petrof@mcgill.ca.
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
mesh_terms: D000818:Animals; D005260:Female; D019695:Glycyrrhizic Acid / Q000008:administration & dosage; D006801:Humans; D007113:Immunity, Innate; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000276:immunology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019695:Glycyrrhizic Acid