Human Molecular Genetics Advance Access originally published online on April 21, 2008
Human Molecular Genetics 2008 17(15):2280-2292; doi:10.1093/hmg/ddn129
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Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy
1 Department of Physiological Science 2 Molecular, Cellular & Integrative Physiology Program 3 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA 4 Division of Pulmonary Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA 5 Animal Science Department, Chonnam National University, Gwangju, Korea
* To whom correspondence should be addressed at: Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, CA 90095-1606, USA. Tel: +1 3102063395; Fax: +1 3108258489; Email: jtidball{at}physci.ucla.edu
Received February 29, 2008; Accepted April 15, 2008
The immune response to dystrophin-deficient muscle promotes the pathology of Duchenne muscular dystrophy (DMD) and the mdx mouse model of DMD. In this investigation, we find that the release of major basic protein (MBP) by eosinophils is a prominent feature of DMD and mdx dystrophy and that eosinophils lyse muscle cells in vitro by the release of MBP-1. We also show that eosinophil depletions of mdx mice by injections of anti-chemokine receptor-3 reduce muscle cell lysis, although lysis of mdx muscle membranes is not reduced by null mutation of MBP-1 in vivo. However, ablation of MBP-1 expression in mdx mice produces other effects on muscular dystrophy. First, fibrosis of muscle and hearts, a major cause of mortality in DMD, is greatly reduced by null mutation of MBP-1 in mdx mice. Furthermore, either ablation of MBP-1 or eosinophil depletion causes large increases in cytotoxic T-lymphocytes (CTLs) in mdx muscles. The increase in CTLs in MBP-1-null mice does not reflect a general shift toward a Th1 inflammatory response, because the mutation had no significant effect on the expression of interferon-gamma, inducible nitric oxide synthase or tumor necrosis factor. Rather, MBP-1 reduces the activation and proliferation of splenocytes in vitro, indicating that MBP-1 acts in a more specific immunomodulatory role to affect the inflammatory response in muscular dystrophy. Together, these findings show that eosinophil-derived MBP-1 plays a significant role in regulating muscular dystrophy by attenuating the cellular immune response and promoting tissue fibrosis that can eventually contribute to increased mortality.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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