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Divergent impact of Toll‐like receptor 2 deficiency on repair mechanisms in healthy muscle versus Duchenne muscular dystrophy
Author(s) -
Mojumdar Kamalika,
Giordano Christian,
Lemaire Christian,
Liang Feng,
Divangahi Maziar,
Qureshi Salman T,
Petrof Basil J
Publication year - 2016
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4689
Subject(s) - innate immune system , duchenne muscular dystrophy , skeletal muscle , inflammation , tlr2 , macrophage , macrophage polarization , biology , medicine , immunology , pathology , immune system , endocrinology , genetics , in vitro
Injury to skeletal muscle, whether acute or chronic, triggers macrophage‐mediated innate immunity in a manner which can be either beneficial or harmful for subsequent repair. Endogenous ligands for Toll‐like receptor 2 ( TLR2 ) are released by damaged tissues and might play an important role in activating the innate immune system following muscle injury. To test this hypothesis, we compared macrophage behaviour and muscle repair mechanisms in mice lacking TLR2 under conditions of either acute (cardiotoxin‐induced) or chronic (mdx mouse genetic model of Duchenne muscular dystrophy; DMD ) muscle damage. In previously healthy muscle subjected to acute damage, TLR2 deficiency reduced macrophage numbers in the muscle post‐injury but did not alter the expression pattern of the prototypical macrophage polarization markers iNOS and CD206 . In addition, there was abnormal persistence of necrotic fibres and impaired regeneration in TLR2 −/− muscles after acute injury. In contrast, TLR2 ablation in chronically diseased muscles of mdx mice not only resulted in significantly reduced macrophage numbers but additionally modified their phenotype by shifting from inflammatory ( iNOS pos CD206 neg ) to more anti‐inflammatory ( iNOS neg CD206 pos ) characteristics. This decrease in macrophage‐mediated inflammation was associated with ameliorated muscle histopathology and improved force‐generating capacity of the dystrophic muscle. Our results suggest that the role of TLR2 in macrophage function and skeletal muscle repair depends greatly upon the muscle injury context, and raise the possibility that inhibition of TLR2 could serve as a useful therapeutic measure in DMD . Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.