Roles of mast cells in the pathogenesis of inflammatory myopathy
- Masaya Yokota†1,
- Kotaro Suzuki†1Email author,
- Koji Tokoyoda2,
- Kazuyuki Meguro1,
- Junichi Hosokawa1,
- Shigeru Tanaka1,
- Kei Ikeda1,
- Takashi Mikata3,
- Toshinori Nakayama2, 4,
- Hitoshi Kohsaka5 and
- Hiroshi Nakajima1Email author
© Yokota et al.; licensee BioMed Central Ltd. 2014
Received: 14 August 2013
Accepted: 5 March 2014
Published: 17 March 2014
In addition to the pivotal roles of mast cells in allergic diseases, recent data suggest that mast cells play crucial roles in a variety of autoimmune responses. However, their roles in the pathogenesis of autoimmune skeletal muscle diseases have not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the roles of mast cells in the development of autoimmune skeletal muscle diseases.
The number of mast cells in the affected muscle was examined in patients with dermatomyositis (DM) or polymyositis (PM). The susceptibility of mast cell-deficient WBB6F1-KitW/KitWv mice (W/Wv mice) to a murine model of polymyositis, C protein-induced myositis (CIM), was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/Wv mice to CIM was also evaluated.
The number of mast cells in the affected muscle increased in patients with PM as compared with patients with DM. W/Wv mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The number of CD8+ T cells and macrophages in the skeletal muscles of CIM decreased in W/Wv mice compared with WT mice. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/Wv mice. Vascular permeability in the skeletal muscle was elevated in WT mice but not in W/Wv mice upon CIM induction.
Mast cells are involved in the pathogenesis of inflammatory myopathy.
Mast cells have long been recognized as the major effector cells in allergic diseases such as asthma, allergic rhinitis, and urticaria [1, 2]. In addition, recent studies have revealed new roles of mast cells in the pathogenesis of autoimmune disease models (reviewed in ), including autoantibody-mediated arthritis , experimental allergic encephalomyelitis , and insulin-dependent diabetes mellitus . Various aspects of mast cell functions in tissue-specific autoimmune diseases might be due to its distribution in anatomical sites such as joints, central nervous system, and pancreas. Although mast cells are also located in skeletal muscle , their roles in the pathogenesis of skeletal muscle diseases have not been clarified.
Dermatomyositis (DM) and polymyositis (PM) are autoimmune myopathies characterized clinically by proximal muscle weakness, muscle inflammation and destruction, and responsiveness to immunosuppressive agents . DM is characterized pathologically by the presence of atrophic, degenerating, or regenerating myofibers and inflammatory cells, composed of B cells along with a small number of CD4+ plasmacytoid dendritic cells, within the perifascicular areas . On the other hand, PM is characterized by the presence of inflammatory cells in the endomysium of skeletal muscle, which are largely composed of CD8+ T cells and macrophages . Recently, Sugihara et al. have established a murine model of polymyositis, which is called C protein-induced myositis (CIM) , and have shown that mice with CIM show pathological features similar to human polymyositis, including a massive infiltration of CD8+ T cells and macrophages in the endomysium of skeletal muscle .
In this study, to address the role of mast cells in the pathogenesis of autoimmune skeletal muscle diseases, we quantified mast cell numbers in muscle tissue samples obtained by muscle biopsies from patients with DM or PM. We also examined the role of mast cells in the pathogenesis of CIM. Our findings suggest that mast cells are involved in the pathogenesis of inflammatory myopathy.
Materials and methods
Patients and samples
Fifteen patients with DM and 12 patients with PM, who were admitted to Chiba University Hospital or National Hospital Organization Shimoshizu Hospital between 2004 and 2012 because of newly diagnosed DM/PM according to the criteria developed by Bohan and Peter [11, 12], were enrolled in this study. The study design was approved by the ethics committees of Chiba University Hospital and Shimoshizu Hospital. Muscle specimens were obtained by muscle biopsy from biceps brachii or quadriceps femoris of the patients before treatment. All patients provided written informed consent. As controls, muscle samples from patients with muscular dystrophy—Becker muscular dystrophy (n = 3) and Limb-Girdle muscular dystrophy (n = 3)—were also analyzed.
Mast cell staining
Sections of muscle samples were fixed and stained with toluidine blue in accordance with a standard protocol. In some experiments, sections of muscle samples were stained with anti-human mast cell tryptase antibody (AA1; Dako Denmark A/S, Glostrup, Denmark) in accordance with the instructions of the manufacturer.
Sections of muscle samples were fixed and stained with hematoxylin-eosin (H&E) in accordance with the standard protocol. The intensity of inflammatory infiltrate was evaluated by semi-quantitative scoring system (5-point grading) as described previously .
Genetically mast cell-deficient WBB6F1-KitW/KitWv mice (W/Wv mice), congenic WBB6F1-Kit+/Kit+ mice, and C57BL/6 J mice were purchased from SLC (Shizuoka, Japan). Enhanced green fluorescent protein transgenic (eGFP-Tg) mice were previously described . All mice were housed in microisolator cages under specific pathogen-free conditions, and all experiments were performed in accordance with the guidelines of Chiba University. Experimental procedures were approved by biomedical research ethics committee of the Graduate School of Medicine at Chiba University (approval ID A22-149).
Induction of C protein-induced myositis
Recombinant murine skeletal C protein fragment 2 was prepared as described previously . For the induction of CIM, 8- to 10-week-old female mice were immunized intradermally at the back and foodpads with 200 μg of the C protein fragment 2 emulsified in complete Freund’s adjuvant (CFA) containing 100 μg of heat-killed Mycobacterium butyricum (Difco, Detroit, MI, USA). Pertussis toxin (0.5 μg/mouse; Seikagaku Kogyo, Tokyo, Japan) was injected to the mice intraperitoneally at the same time. As a control, mice were injected intradermally with CFA in the absence of C protein fragment 2 and injected intraperitoneally with pertussis toxin. At indicated days after the induction of CIM, histological analysis was performed on proximal muscles (hamstrings and quadriceps). Histological scores were evaluated by a pathologist in a blinded manner as described previously . Necrotic muscle fibers were defined by decreased H&E staining intensity, which was occasionally accompanied by mononuclear cell infiltration in regenerative processes, and total necrotic area was evaluated as described previously . In preliminary experiments, we confirmed necrotic muscle fibers by investigating serial sections of muscle samples with H&E staining and nicotinamide adenine dinucleotide hydrogen-tetrazolium reductase (NADH-TR) staining (data not shown).
Quantification of degranulating mast cells in skeletal muscle
At indicated days after the induction of CIM, mast cells in the skeletal muscle were assessed for intact phenotype versus degranulating phenotype in a blinded manner by using morphologic criteria as described previously . In brief, mast cells were identified as cells containing granules stained with toluidine blue. Degranulating cells were defined by the presence of granules outside the cell border with coincident vacant granule space within the cell border. Only cells in which a nucleus was present were counted.
Detection of CD8+ T cells and macrophages at the sites of C protein-induced myositis
Twenty-one days after the induction of CIM, a block of proximal muscles (hamstring and quadriceps) was fixed overnight in 4% paraformaldehyde in phosphate-buffered saline (PBS), equilibrated in 30% sucrose in PBS, embedded in OCT compound, and kept at −80°C. Cryosections were stained with anti-CD8 antibody (53-6-7; BD PharMingen, San Diego, CA, USA) or anti-F4/80 antibody (BM8; eBioscience, San Diego, CA, USA). After washing, sections were stained with TO-PRO-3 iodide (Invitrogen, San Diego, CA, USA) for nuclear staining and analyzed by using LSM 710 confocal laser microscopy (Carl Zeiss Microimaging, Oberkochen, Germany).
Reconstitution of mast cells in W/Wv mice with bone marrow-derived mast cells
Primary culture of interleukin-3-dependent bone marrow-derived mast cells (BMMCs) was prepared from 6- to 8-week-old eGFP-Tg mice and maintained as previously described . Cultured BMMCs from eGFP-Tg mice were harvested and injected intravenously into W/Wv mice (1 × 107 cells per mouse). Four weeks after the transplantation, CIM was induced in these mice.
Detection of engrafted mast cells from eGFP-Tg mice in skeletal muscle
Four weeks after the transfer of BMMCs prepared from eGFP-Tg mice, a block of proximal muscles was fixed, equilibrated, and embedded in OCT compound as described above. Cryosections were stained with TO-PRO-3 iodide, and the presence of eGFP+ cells was analyzed by using LSM 710.
Evaluation of vascular permeability
Vascular permeability was evaluated as described elsewhere . In brief, at indicated days after CIM induction, Evans blue dye (1% in saline, 100 μL/mouse) was intravenously injected into mice under anesthesia with pentobarbital (100 mg/kg). Forty minutes later, mice were perfused intracardially with PBS until no more efflux of blue dye was seen in the right atrium. A block of proximal muscles was fixed and embedded in OCT compound as described above. The leakage of Evans blue dye in the tissue was assessed by the presence of red fluorescence of Evans blue dye in extravascular spaces by using LSM 710 and was quantified with National Institutes of Health ImageJ software.
Evaluation of anti-C protein antibodies
The levels of anti-C protein antibodies in sera were evaluated by enzyme-linked immunosorbent assay. In brief, recombinant C protein (10 μg/mL in 0.05% Tween 20 in PBS) was adsorbed onto flat-bottomed microtiter plates overnight at 4°C. After blocking with 1% bovine serum albumin in PBS, plates were incubated with sera diluted at the indicated ratio in 0.05% Tween 20 in PBS. Anti-C protein antibodies bound to the plate coated with C protein were detected by using alkaline phosphatase-conjugated, affinity-purified antibody against IgE, IgG, IgG1, IgG2a, IgG2b, IgG2c, and IgG3 (SouthernBiotech, Birmingham, AL, USA). Assays were developed with phosphatase substrate (Sigma-Aldrich, St. Louis, MO, USA), stopped with 0.6 M NaOH, and read at a wavelength of 405 nm on a microplate reader.
Data are summarized as mean ± standard deviation (SD) or median (interquartile range). The statistical analysis of the results was performed by an unpaired t test, a Wilcoxon test, Fisher’s exact test, or a Spearman rank correlation coefficient as appropriate. P values of less than 0.05 were considered significant.
The numbers of mast cells are increased in muscle samples of patients with polymyositis
Characteristics of the patients with dermatomyositis/polymyositis
n = 15
n = 12
Sex, % female
Disease duration, months
Anti-nuclear Ab-positive, %
MMT score, 0-90
Number of patients with ILD, %
Allergic disease, %
The susceptibility to C protein-induced myositis is attenuated in mast cell-deficient W/Wv mice
Kinetic analysis of the numbers of mast cells in skeletal muscle in wild-type mice upon C protein-induced myositis induction
Days after immunization
6.3 ± 1.0
10.5 ± 3.7
13.5 ± 7.4a
2.2 ± 1.0
3.3 ± 1.0
5.0 ± 3.6a
1.3 ± 1.3
3.3 ± 1.0
2.8 ± 0.5a
Infiltration of CD8+ T cells and macrophages in skeletal muscle is reduced in C protein-induced myositis in W/Wv mice
C protein-specific IgGs are similarly produced in wild-type mice and W/Wv mice upon C protein-induced myositis induction
The susceptibility to C protein-induced myositis is restored in mast cell-engrafted W/Wv mice
Vascular leakage in skeletal muscle is detected in wild-type mice but not in W/Wv mice upon C protein-induced myositis induction
In this study, we show that mast cells are involved in the pathogenesis of inflammatory myopathy. We found that the number of mast cells in the affected muscle was increased in patients with PM as compared with that in patients with DM (Figure 1b). We also found that the number of degranulating mast cells was increased in the endomysium of skeletal muscle upon CIM induction (Figure 2b). Moreover, we found that the susceptibility to CIM was reduced in mast cell-deficient W/Wv mice as compared with WT mice (Figures 3 and 4) and that the reduced susceptibility of W/Wv mice to CIM was restored by the reconstitution of mast cells (Figure 6). Taken together, these results suggest that mast cells play roles in the pathogenesis of PM.
We show that the number of mast cells is increased in the affected muscles in patients with PM. Although DM and PM share many clinical characteristics such as proximal muscle weakness, muscle inflammation, and extramuscular manifestations (including interstitial lung disease), the histopathologic features of the affected muscle are different between DM and PM . DM is characterized by the presence of atrophic, degenerating, or regenerating myofibers within the perifascicular areas , whereas PM is characterized by the presence of inflammatory cells in the endomysium of skeletal muscle, which are largely composed of CD8+ T cells and macrophages . In addition, we showed that the number of mast cells in the affected muscle was increased in PM as compared with that in DM (Figure 1b). On the other hand, a recent study has suggested that plasmacytoid dendritic cells play an important role in the pathogenesis of DM . Taken together, these data suggest that critical effector cells are different in the pathogenesis of DM and PM.
We show a crucial role of mast cells in causing CIM. Although it has long been known that mast cells exist in skeletal muscle , pathophysiological significance of mast cells in skeletal muscle has not been clarified. Mast cells are critical effector cells in allergic diseases and other IgE-associated acquired immune responses, including protection against parasites [1, 23]. In addition, recent studies have revealed that mast cells are involved in the pathogenesis of autoimmune disease models [3, 4]. On the other hand, in some circumstances, mast cells exhibit anti-inflammatory and immunosuppressive functions [24, 25], suggesting that mast cells have both positive and negative impacts on immune responses. We found that mast cell-deficient W/Wv mice exhibited reduced susceptibility to CIM as compared with WT mice (Figures 3 and 4) and that the reduced susceptibility of W/Wv mice was restored by the reconstitution of mast cells (Figure 6). Although we could not exclude the possibility that other abnormalities of W/Wv mice such as anemia and reduced numbers of neutrophils and basophils [1, 26] are also involved in the reduced susceptibility to CIM, our results strongly suggest that mast cells in skeletal muscle play an important role in the development of CIM.
Regarding the mechanism underlying mast cell-mediated exacerbation of autoimmune diseases, Binstadt et al. have shown an attractive mechanism for achieving organ-specific autoimmune diseases, in which mast cells increase disease severity by enhancing vascular permeability at the site of inflammation . The authors have demonstrated that arthritogenic antibodies activate mast cells and that histamine and serotonin released from activated mast cells increase vascular permeability at the site and are destined to develop arthritis . Here, we found an increase of vascular permeability in the endomysium of skeletal muscle in WT mice but not in W/Wv mice upon CIM induction (Figure 7). Notably, an increase of vascular permeability was detected in WT mice at 10 days after the induction, when degranulating mast cells in skeletal muscle were increased (Figure 2b). These data suggest that mast cells promote the recruitment of inflammatory cells into the endomysium of skeletal muscle in CIM in part by increasing vascular permeability.
Accumulating evidence has shown that muscle injury in patients with PM is driven by cytotoxic CD8+ T cells . In CIM, recent studies have also shown that CD8+ T cells are accumulated at the site of inflammation and play a critical role in muscle injury in a perforin-dependent manner [10, 16]. In this study, we found that the numbers of CD8+ T cells were reduced in the affected muscle in CIM in mast cell-deficient W/Wv mice (Figure 4). We also found that inflammatory cell infiltration and necrotic muscle area were significantly reduced in W/Wv mice as compared with those in WT mice (Figure 3). These findings suggest that the impaired infiltration of CD8+ T cells into the inflammatory sites is involved in the reduced susceptibility of W/Wv mice to CIM.
We also show that the numbers of macrophages in the affected muscle in CIM are reduced in W/Wv mice (Figure 4). Regarding the mechanism underlying the reduced accumulation of macrophages at the site of CIM in W/Wv mice, we found that the expression of monocyte chemoattractant protein-1 (MCP-1) in skeletal muscle was reduced in W/Wv mice as compared with that in WT mice (data not shown). It has been shown that mast cells produce MCP-1 and induce the accumulation of macrophages in a murine model of asthma . In preliminary experiments, we also found that MCP-1-expressing mast cells were detected at the site of CIM in W/Wv mice engrafted with eGFP+ BMMCs (data not shown). Therefore, it is suggested that mast cells directly induce the accumulation of macrophages at the sites of CIM through the production of MCP-1.
At present, the signal that activates mast cells at the site of CIM remains unknown. The importance of Fc receptor family members expressed on mast cells has been revealed in other models of autoimmune diseases such as experimental allergic encephalomyelitis  and K/BxN arthritis . In this regard, however, it has been shown that CIM is normally induced in mice lacking B cells , indicating that immunoglobulins are not required for the development of CIM. The possibility that mast cells are activated by some endogenous danger signals that possess proinflammatory potential need to be addressed in the future.
Our results indicate that mast cells play a role in the pathogenesis of inflammatory myopathy. Although further studies are required, our results should add a new insight into the pathophysiological roles of mast cells in autoimmune diseases and suggest that mast cells could be possible therapeutic targets in patients with PM.
bone marrow-derived mast cell
complete Freund’s adjuvant
C protein-induced myositis
enhanced green fluorescent protein
enhanced green fluorescent protein transgenic
monocyte chemoattractant protein-1
- W/Wv mice:
We thank Juri Iwata for technical support. This work was supported in part by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government, and by the LGS (Leading Graduate School) Program, MEXT, Japan.
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