Role of Toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle.

Mark McIntosh,'s picture
PubMed URL: 
http://www.ncbi.nlm.nih.gov/pubmed/24368419
Author: 
Nagaraju K
Author List: 
Henriques-Pons A
Yu Q
Rayavarapu S
Cohen TV
Ampong B
Cha HJ
Jahnke V
Van der Meulen J
Wang D
Jiang W
Kandimalla ER
Agrawal S
Spurney CF
Nagaraju K
Journal: 
Hum Mol Genet
PubMed ID: 
24368419
Pagination: 
2604-17
Volume: 
23
Issue: 
10
Abstract: 
Although the cause of Duchenne muscular dystrophy (DMD) is known, the specific factors that initiate and perpetuate disease progression are not well understood. We hypothesized that leaky dystrophin-deficient skeletal muscle releases endogenous danger signals (TLR ligands), which bind to Toll-like receptors (TLRs) on muscle and immune cells and activate downstream processes that facilitate degeneration and regeneration in dystrophic skeletal muscle. Here, we demonstrate that dystrophin-deficient mouse muscle cells show increased expression of several cell-surface and endosomal TLRs. In vitro screening identified ssRNA as a relevant endogenous TLR7 ligand. TLR7 activation led to myd88-dependent production of pro-inflammatory cytokines in dystrophin-deficient muscle cells, and cause significant degeneration/regeneration in vivo in mdx mouse muscle. Also, knockout of the central TLR adaptor protein, myd88 in mdx mice significantly improved skeletal and cardiac muscle function. Likewise, proof-of-concept experiments showed that treating young mdx mice with a TLR7/9 antagonist significantly reduced skeletal muscle inflammation and increased muscle force, suggesting that blocking this pathway may have therapeutic potential for DMD.
Published Date: 
May, 2014

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