Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy

Michelle Wehling-henricks, Sophie Sokolow, Jamie J. Lee, Kyu H. Myung, S. Armando Villalta, James G. Tidball

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2280-2292
Number of pages13
JournalHuman Molecular Genetics
Volume17
Issue number15
DOIs
StatePublished - Aug 2008

Fingerprint

Muscular Dystrophies
Cellular Immunity
Fibrosis
Inbred mdx Mouse
Eosinophil Major Basic Protein
Duchenne Muscular Dystrophy
Muscles
Proteins
Cytotoxic T-Lymphocytes
Eosinophils
Muscle Cells
Mutation
Dystrophin
Mortality
Chemokine Receptors
Nitric Oxide Synthase Type II
Interferon-gamma
Myocardium
Tumor Necrosis Factor-alpha
Pathology

ASJC Scopus subject areas

  • Genetics

Cite this

Wehling-henricks, M., Sokolow, S., Lee, J. J., Myung, K. H., Villalta, S. A., & Tidball, J. G. (2008). Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. Human Molecular Genetics, 17(15), 2280-2292. https://doi.org/10.1093/hmg/ddn129

Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. / Wehling-henricks, Michelle; Sokolow, Sophie; Lee, Jamie J.; Myung, Kyu H.; Villalta, S. Armando; Tidball, James G.

In: Human Molecular Genetics, Vol. 17, No. 15, 08.2008, p. 2280-2292.

Research output: Contribution to journalArticle

Wehling-henricks, M, Sokolow, S, Lee, JJ, Myung, KH, Villalta, SA & Tidball, JG 2008, 'Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy', Human Molecular Genetics, vol. 17, no. 15, pp. 2280-2292. https://doi.org/10.1093/hmg/ddn129
Wehling-henricks, Michelle ; Sokolow, Sophie ; Lee, Jamie J. ; Myung, Kyu H. ; Villalta, S. Armando ; Tidball, James G. / Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 15. pp. 2280-2292.
@article{57c0709447a844138618ff389878cd62,
title = "Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy",
abstract = "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.",
author = "Michelle Wehling-henricks and Sophie Sokolow and Lee, {Jamie J.} and Myung, {Kyu H.} and Villalta, {S. Armando} and Tidball, {James G.}",
year = "2008",
month = "8",
doi = "10.1093/hmg/ddn129",
language = "English (US)",
volume = "17",
pages = "2280--2292",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "15",

}

TY - JOUR

T1 - Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy

AU - Wehling-henricks, Michelle

AU - Sokolow, Sophie

AU - Lee, Jamie J.

AU - Myung, Kyu H.

AU - Villalta, S. Armando

AU - Tidball, James G.

PY - 2008/8

Y1 - 2008/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=48049084529&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=48049084529&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddn129

DO - 10.1093/hmg/ddn129

M3 - Article

C2 - 18430716

AN - SCOPUS:48049084529

VL - 17

SP - 2280

EP - 2292

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 15

ER -