Abstract
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness which is ultimately fatal, most often due to involvement of the diaphragm. Macrophage infiltration of dystrophic muscles has been strongly linked to muscle damage and fibrosis in DMD. We hypothesized that cenicriviroc (CVC), a dual chemokine receptor (CCR2/CCR5) antagonist currently under clinical evaluation for other diseases, could prevent macrophage accumulation and blunt disease progression in the diaphragms of mdx mice (genetic homologue of DMD). Treatment with CVC (20 mg/kg/day intraperitoneally) or vehicle was initiated in mdx mice at 2 weeks of age (prior to the onset of muscle necrosis) and continued for 4 weeks. Flow cytometry to assess inflammatory cell subsets as well as histological and force generation parameters were determined in mdx diaphragms at the conclusion of the treatment. CVC therapy induced a major (3.9-fold) reduction in total infiltrating macrophages, whereas total numbers of neutrophils and T lymphocytes (CD4+ and CD8+) were unaffected. No changes in macrophage polarization status (inflammatory versus anti-inflammatory skewing based on iNOS and CD206 expression) were observed. Muscle fiber size and fibrosis were not altered by CVC, whereas a significant reduction in centrally nucleated fibers was found suggesting a decrease in prior necrosis-regeneration cycles. In addition, maximal isometric force production by the diaphragm was increased by CVC therapy. These results suggest that CVC or other chemokine receptor antagonists which reduce pathological macrophage infiltration may have the potential to slow disease progression in DMD.
Highlights
Duchenne Muscular Dystrophy (DMD) is the most common X-linked lethal disorder in humans affecting up to 1 in 3500 live male births, with about a third of cases being due to new spontaneous mutations in the dystrophin gene [1]
Blockade of the NF-kB pathway can ameliorate the disease [3,29], and several inflammatory mediators associated with innate immunity such as TNF-alpha and inducible nitric oxide synthase [30,31] play important roles in promoting early muscle damage
The CC class chemokines which are ligands for CCR2 and CCR5 are expressed at abnormally high levels in DMD muscles [8,32,33]
Summary
Duchenne Muscular Dystrophy (DMD) is the most common X-linked lethal disorder in humans affecting up to 1 in 3500 live male births, with about a third of cases being due to new spontaneous mutations in the dystrophin gene [1]. There is an urgent need for more efficacious therapies that help to arrest DMD disease progression while minimizing adverse side effects Both animal model and human data indicate that dysregulated inflammatory mechanisms play an important role in driving DMD from its earliest stages [3]. Germline ablation of CCR2 in mdx mice improved multiple muscle parameters including force generation, and similar benefits occurred when mdx mice were treated with a CCR2-inhibiting fusion protein molecule [6]. Another chemokine receptor, CCR5, as well as its major ligands CCL3 (MIP-1α) and CCL5 (RANTES), are highly upregulated in mdx muscles [8]. CCR5 has been implicated in monocyte recruitment [9,10,11] as well as in the proinflammatory polarization of macrophages [12], suggesting that it could represent a useful therapeutic target in DMD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
