NF-κB inhibition reveals a novel role for HGF during skeletal muscle repair

J. D. Proto, Y. Tang, A. Lu, W. C.W. Chen, E. Stahl, M. Poddar, S. A. Beckman, P. D. Robbins, L. J. Nidernhofer, K. Imbrogno, T. Hannigan, W. M. Mars, B. Wang, J. Huard

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23 Scopus citations

Abstract

The transcription factor nuclear factor ?B (NF-κB)/p65 is the master regulator of inflammation in Duchenne muscular dystrophy (DMD). Disease severity is reduced by NF-κB inhibition in the mdx mouse, a murine DMD model; however, therapeutic targeting of NF-κB remains problematic for patients because of its fundamental role in immunity. In this investigation, we found that the therapeutic effect of NF-κB blockade requires hepatocyte growth factor (HGF) production by myogenic cells. We found that deleting one allele of the NF-κB subunit p65 (p65+/-) improved the survival and enhanced the anti-inflammatory capacity of muscle-derived stem cells (MDSCs) following intramuscular transplantation. Factors secreted from p65+/- MDSCs in cell cultures modulated macrophage cytokine expression in an HGF-receptor-dependent manner. Indeed, we found that following genetic or pharmacologic inhibition of basal NF-κB/p65 activity, HGF gene transcription was induced in MDSCs. We investigated the role of HGF in anti-NF-κB therapy in vivo using mdx;p65+/- mice, and found that accelerated regeneration coincided with HGF upregulation in the skeletal muscle. This anti-NF-κB-mediated dystrophic phenotype was reversed by blocking de novo HGF production by myogenic cells following disease onset. HGF silencing resulted in increased inflammation and extensive necrosis of the diaphragm muscle. Proteolytic processing of matrix-associated HGF is known to activate muscle stem cells at the earliest stages of repair, but our results indicate that the production of a second pool of HGF by myogenic cells, negatively regulated by NF-κB/p65, is crucial for inflammation resolution and the completion of repair in dystrophic skeletal muscle. Our findings warrant further investigation into the potential of HGF mimetics for the treatment of DMD.

Original languageEnglish (US)
Article numbere1730
JournalCell Death and Disease
Volume6
Issue number4
DOIs
StatePublished - Apr 23 2015

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    Proto, J. D., Tang, Y., Lu, A., Chen, W. C. W., Stahl, E., Poddar, M., Beckman, S. A., Robbins, P. D., Nidernhofer, L. J., Imbrogno, K., Hannigan, T., Mars, W. M., Wang, B., & Huard, J. (2015). NF-κB inhibition reveals a novel role for HGF during skeletal muscle repair. Cell Death and Disease, 6(4), [e1730]. https://doi.org/10.1038/cddis.2015.66