Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype.
In the degenerative disease Duchenne muscular dystrophy, inflammatory cells enter muscles in response to repetitive muscle damage. Immune factors are required for muscle regeneration, but chronic inflammation creates a profibrotic milieu that exacerbates disease progression. Osteopontin (OPN) is an immunomodulator highly expressed in dystrophic muscles. Ablation of OPN correlates with reduced fibrosis and improved muscle strength as well as reduced natural killer T (NKT) cell counts. Here, we demonstrate that the improved dystrophic phenotype observed with OPN ablation does not result from reductions in NKT cells. OPN ablation skews macrophage polarization toward a pro-regenerative phenotype by reducing M1 and M2a and increasing M2c subsets. These changes are associated with increased expression of pro-regenerative factors insulin-like growth factor 1, leukemia inhibitory factor, and urokinase-type plasminogen activator. Furthermore, altered macrophage polarization correlated with increases in muscle weight and muscle fiber diameter, resulting in long-term improvements in muscle strength and function in mdx mice. These findings suggest that OPN ablation promotes muscle repair via macrophage secretion of pro-myogenic growth factors.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Molecular, Cellular, and Integrative Physiology Interdepartmental PhD Program, University of California, Los Angeles, Los Angeles, CA 90095.
Joana
J
Capote
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 mspencer@mednet.ucla.edu ikramero@ucla.edu.
Irina
I
Kramerova
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
Leonel
L
Martinez
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
Sylvia
S
Vetrone
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611 Wellstone Muscular Dystrophy Center, University of Florida, Gainesville, FL 32610.
Elisabeth R
ER
Barton
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610 Wellstone Muscular Dystrophy Center, University of Florida, Gainesville, FL 32610.
H Lee
HL
Sweeney
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095 Wellstone Muscular Dystrophy Center, University of Florida, Gainesville, FL 32610.
M Carrie
MC
Miceli
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095 Wellstone Muscular Dystrophy Center, University of Florida, Gainesville, FL 32610 mspencer@mednet.ucla.edu ikramero@ucla.edu.
Melissa J
MJ
Spencer
D000818:Animals; D016764:Cell Polarity; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000473:pathology*; D055611:Natural Killer T-Cells / Q000378:metabolism / Q000502:physiology; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D012038:Regeneration
D053495:Osteopontin