Dermatomyositis (DM) is a type of idiopathic inflammatory myopathy (IM), which affects the skin, muscle and other organs, and is associated with significant morbidity and mortality (1). The incidence of DM is estimated at 9.63 cases per million individuals, according to a population-based study (2). DM affects children and adults, and occurs more commonly in female patients (3). DM is closely associated with an increased risk of malignancy (4), including ovarian, lung, pancreatic, stomach and colorectal cancers, and non-Hodgkin's lymphoma (5). The rarity of the disease, the different features of the multiple disease subsets, and the lethal complications associated with DM make it difficult to cure (6).

Several factors are thought to contribute to DM, including environmental factors and genetic susceptibility. The association between DM and various environmental triggers, including medication, sunlight and infection, have been examined (7). In addition, a genetic component may predispose individuals to DM; the most important genetic region associated with DM appears to be the major histocompatibility complex (MHC), and a few candidate genes, such as signal transducer and activator of transcription (STAT) 4 and tumor necrosis factor, have been reported to be relevant to the development of DM (8). The first case of DM was reported in 1875 (9); however, the underlying molecular mechanisms of this disease remain incompletely understood. Pathological studies of muscle tissue in DM have reported histological abnormalities in capillaries, and the infiltration of muscle by B cells, cluster of differentiation (CD)4⁺ T cells, macrophages and plasma cells, and perifascicular atrophy (10). Therefore, DM has classically been considered a humorally mediated autoimmune disease (10). Recently, a microarray study reported that type 1 interferon (IFN)-mediated immune pathogenesis is likely to be involved in DM (11). Identification of the involved molecular mechanisms may lead to the development of effective therapeutic approaches for the treatment of patients with DM.

The present study downloaded the GSE48280 dataset, and identified the differentially expressed genes (DEGs) between the DM and healthy control (HC) muscle tissue samples, in order to explore the molecular mechanisms underlying DM. In addition, functional and pathway enrichment analyses were conducted, and protein-protein interaction (PPI) networks of the DEGs were constructed to identify the key genes and signaling pathways in DM. The findings of the present study may be helpful to improve understanding regarding the pathogenesis of DM, and provide insight into the development of a novel therapeutic strategy.

DM is an autoimmune disease, which seriously impacts the quality of life of affected patients. The underlying pathogenesis of DM remains elusive. The present study analyzed gene expression profiles, identified the DEGs associated with DM, and enabled the identification of potential therapeutic targets. In the present study, 201 DEGs were identified, of which 180 were upregulated and 21 were downregulated. Following GO functional enrichment analysis using ClueGO, the type I IFN signaling pathway was revealed to be the most significantly enriched GO term within the DEGs. Previous studies have reported that patients with DM exhibit an activated type I IFN response, as demonstrated by increased type I IFN activity, and an IFN signature in the muscle, blood and skin (1,18,19), which has also been described in patients with systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and systemic sclerosis (20). In addition, type 1 IFN-producing plasmacytoid dendritic cells are abundant in DM muscle and skin (21). When compared with other types of IM, the overproduction of IFN-I inducible transcripts and proteins in muscle tissue is a unique feature of DM (22). Furthermore, the iatrogenic administration of recombinant IFNs has been reported to induce DM (23). Taken together, these data indicated that the type I IFN signaling pathway may be important in the pathogenesis of DM.

A KEGG pathway enrichment analysis of the DEGs was conducted, and 27 significantly enriched pathways were identified. The majority of these pathways can be divided into two categories: Infectious diseases and the immune system. The enriched immune system-related pathways include antigen processing and presentation, complement and coagulation cascades pathway, RIG-I-like receptor (RLR) signaling pathway, Toll-like receptor (TLR) signaling pathway, and cytosolic DNA-sensing pathway. Among them, the TLR signaling, RLR signaling and cytosolic DNA-sensing pathways are responsible for detecting pathogens and generating innate immune responses. Type I IFNs are primarily induced by the activation of pattern-recognition receptors, such as TLRs, RLRs and cytoplasmic DNA sensor receptors (24). In the present study, chemokine (C-C motif) ligand 5 (CCL5), CD14, C-X-C motif chemokine 10 (CXCL10), CXCL11, STAT1 and TLR3 DEGs were enriched in the TLR signaling pathway, whereas CXCL10, CYLD lysine 63 deubiquitinase, DEXD/H-Box helicase 58 (DDX58), interferon induced with helicase C domain 1 (IFIH1), ISG15 and tripartite motif-containing protein 25 DEGs were enriched in the RLR signaling pathway. Furthermore, ADAR, CCL5, CXCL10 and DDX58 DEGs participated in the cytosolic DNA-sensing pathway. CCL5 is a key proinflammatory chemokine, which may have a role in driving recruitment of leukocytes, angiogenesis and fibrosis in chronic inflammatory diseases. Furthermore, CCL5 blockade is able to prevent immunopathology (25). CXCL10 and CXCL11 are members of the CXC subfamily of chemokines. Serum levels of CXCL10 are elevated in patients with active DM (26). CXCL10 has also been reported to be secreted by human skeletal muscle cells, which promote inflammation (27). A previous study using an animal model of C-protein-induced myositis demonstrated that suppressing CXCL10 with monoclonal antibodies was able to inhibit muscular inflammation (28). TLR3 is a member of the TLR family, which has a fundamental role in pathogen recognition and activation of innate immunity. An in vitro study revealed that TLR3 is involved in the overexpression of MHC-I in IM (29). Cappelletti et al reported that TLR3 is localized on vascular endothelial cells, muscle infiltrating cells and regenerating myofibers in DM (30). In addition, Li et al (31) demonstrated that TLR-3 and RIG-I are implicated in the formation of perifascicular atrophy in DM.

RLRs comprise DDX58 (RIG-I), IFIH1 [also known as melanoma differentiation-associated protein 5 (MDA5)] and LGP2, and are known as cytosolic RNA receptors that induce the expression of type I IFN genes. Sato et al (32) detected anti-clinically amyopathic DM (CADM)-140 antibodies encoded by MDA5 in patients with amyopathic DM; of these patients, 50% had rapidly progressive interstitial lung disease (RP-ILD). In addition, it has been reported that anti-MDA5 autoantibodies may be useful for diagnosing DM, particularly the CADM and RP-ILD subsets among Asian cohorts (33). Suárez-Calvet et al (12) reported that RIG-I was upregulated in pathological muscle fibers from patients with DM compared with other types of IM, as determined by immunohistochemistry. In addition, human myotubes were shown to produce IFN-β in response to RIG-I stimulation, and the autocrine effects of IFN-β could further amplify the expression of IFN genes. The results of the present KEGG analysis highlighted the role of the type I IFN signaling pathway in the pathogenesis of DM, and suggested that DEGs associated with these pathways, including CCL5, CXCL10, TLR3, DDX58 and IFIH1, may be used as potential targets for DM diagnosis and treatment.

Hub nodes have more complex interactions compared with other genes, thus indicating that they have important roles in the underlying mechanisms of disease (34). Therefore, identification of hub genes may facilitate the development of effective therapeutic approaches for the treatment of patients with DM. The following DEGs: ISG15, IRF1, IFIT1, HLA-A, HLA-B, HLA-C, GBP2, IRF9, OASL, OAS1, OAS2, OAS3, STAT2, IFIT2, IFIT3, MX1, IFITM1, IFITM2, IFITM3, IFI6, IFI27, IFI35, XAF1 and ADAR were identified as hub genes in the PPI networks, thus indicating that these genes may have pivotal roles in DM development. Notably, all of these hub genes are involved in the type I IFN signaling pathway in DM. The ISG15 gene had the highest degree in the PPI networks (degree, 30). Salajegheh et al demonstrated that ISG15 is one of the most upregulated genes in DM muscle compared with normal muscle, and the ISG15 protein localizes to atrophic myofibers, as determined by immunohistochemistry (23). ISG15 is a ubiquitin-like modifier (35), which is believed to function as a possible mediator of muscle atrophy via protein conjugation, and may contribute to disease activity in DM. MX1, IFIT1 and IFIT3 have been detected in DM muscle, and have previously been identified as ISG15-conjugated in IFN-β-stimulated HeLa cells (36). Furthermore, MX1 is an IFN-I-induced protein that provides innate defense against several viruses. A previous study reported that MX1 is abundant in DM muscle and skin, and is specifically expressed in DM but not in other types of IM (37). In addition, MX1 RNA in juvenile DM peripheral blood mononuclear cells is positively correlated with muscle involvement (38). Therefore, ISG15 and MX1 may contribute to disease activity, and may be considered potential molecular markers and effective treatment targets in DM.

Human leukocyte antigen (HLA-A, HLA-B, HLA-C) is the human-specific MHC. A previous study reported that MHC-I antigens were not detected in normal muscle, but were upregulated in IM muscle (39). In transgenic mice, overexpression of MHC-I is sufficient to induce myositis (40). The induction of MHC-I in IM may involve type I IFN and the 'IFN-I signature' is also induced in IMs (10). These data suggested that MHC-I may be considered a useful adjunctive diagnostic test for DM.

Other hub genes associated with the type I IFN signaling pathway may also have an important role in the pathogenesis of DM. For example, the OAS family proteins, which are predominantly induced by IFN type I, consist of OAS1, OAS2, OAS3 and OASL. OAS levels are strongly associated with autoimmune diseases (41). Sanayama et al (42) proposed that OASL may be a biomarker for the response of patients with rheumatoid arthritis to tocilizumab, which is the most commonly used drug to treat this disease. Identification of these genes and their precise roles may clarify the mechanism and offer useful information regarding the treatment of DM.

In conclusion, the present study attempted to explore the potential molecular mechanisms underlying DM using bioinformatics analyses. The findings of the present study may contribute to our understanding regarding the molecular mechanisms underlying DM. The identified DEGs, including CCL5, CXCL10, TLR3, DDX58, IFIH1, ISG15 and MX1, may potentially be used as targets for DM diagnosis and treatment. However, further studies are required to further verify this hypothesis.