Interleukin-6 trans-signalling regulates monocyte chemoattractant protein-1 production in immune-mediated necrotizing myopathy

Abstract

Abstract Objective Immune-mediated necrotizing myopathy (IMNM) is pathologically characterized by diffuse myofibre necrosis and regeneration, myophagocytosis and a sparse inflammatory infiltrate. Monocyte chemoattractant protein-1 (MCP-1) is a key chemokine that regulates monocyte/macrophage infiltration into injured tissues. IL-6 signalling in the induction of MCP-1 expression has not been investigated in IMNM. Methods MCP-1 expression in muscle specimens was assessed using immunohistochemistry and Reverse transcription quantitative polymerase chain reaction (RT-qPCR). Levels of multiple serological cytokines were evaluated using the electrochemiluminescence-based immunoassays. Flow cytometry, RT-qPCR, enzyme-linked immunosorbent assay, western blot, dual-luciferase reporter assays and chromatin immunoprecipitation qPCR were performed to explore the effects of IL-6 signalling on MCP-1 production in human myoblasts. Results MCP-1 was scattered and was positively expressed within myofibres and a few inflammatory cells in the muscles of patients with IMNM. Sarcoplasmic MCP-1 expression significantly correlated with myonecrosis, myoregeneration and inflammatory infiltration. Serum MCP-1, IL-6 and the soluble form of the IL-6 receptor (sIL-6R) were elevated in patients with IMNM compared with controls. Serological MCP-1 levels were significantly associated with serum IL-6 expression and clinical disease severity in IMNM patients. The IL-6/sIL-6R complex induced MCP-1 expression via the signal transducer and activator of transcription 3 (STAT3) pathway in human myoblasts. Mechanistically, phospho-STAT3 was enriched in the MCP-1 promoter region and promoted the transcription. Conclusion IL-6 trans-signalling may contribute to the immunopathogenesis of IMNM by augmenting inflammation through regulation of MCP-1 expression in IMNM.