OP0138 CLUSTERIN ASSOCIATES WITH DISEASE MECHANISMS AND INFLAMMATION IN MYOSITIS PATIENTS

Abstract

Background:Idiopathic inflammatory myopathies (IIM, myositis) are a heterogeneous group of autoimmune muscle disorders characterized by skeletal muscle weakness and damage, inflammation and extramuscular manifestations. Recent findings suggest that immunological as well as nonimmunological processes, such as endoplasmic reticulum stress, hypoxia, mitochondrial and metabolic dysfunction are involved in the pathogenesis of IIMs [1]. Clusterin (CLU) has been reported to play a protective function in the development of tissue injury, inflammation and autoimmunity, and is involved in the maintenance of immune homeostasis [2].Objectives:This study aimed to explore a potential involvement of the circulating levels and skeletal muscle expression of CLU in pathogenic mechanisms of IIM.Methods:A total of 85 IIM patients and 86 healthy controls (HC) were recruited. In addition, 20 IIM patients and 21 HC underwent a muscle biopsy. Circulating concentrations of CLU were measured by ELISA. Serum cytokine profile of patients and HC was assessed by Cytokine 27-plex Assay. Immunohistochemical localisation of CLU was assessed in 10 IIM and 4 control muscle tissue specimens. The expression of CLU and myositis related cytokines in muscle tissue was determined by real-time PCR.Results:We observed a significant increase of circulating CLU in all IIM patients compared to HC (86.2 (71.6-99.0) vs. 59.6 (52.6-68.4) μg/mL, p < 0.0001). Moreover, CLU serum levels were positively correlated with myositis disease activity assessment (MYOACT) (r = 0.337, p = 0.008), myositis intention-to-treat activity index (MITAX) (r = 0.357, p = 0.004) and global disease assessment evaluated by physician (r = 0.309, p = 0.015). In addition to that, a multivariate redundancy analysis revealed a combined effect of serum CLU and cytokine profile (represented by cytokines and chemokines known to be involved in IIM) on disease activity measures. In muscle tissue, CLU mRNA was significantly increased in IIM patients compared to controls (p = 0.032) and correlated with IL-1β (r = 0.489, p = 0.034), IL-6 (r = 0.581, p = 0.009), TNF (r = 0.485, p = 0.035) and PGC-1α (r = 0.709, p = 0.001) mRNA. Immunohistochemistry revealed CLU accumulation in the cytoplasm of regenerating myofibers.Conclusion:Our results show an up-regulation of clusterin in circulation and skeletal muscle of IIM patients that associates with disease activity and inflammation, and its specific expression in regenerating myofibres. Based on our data and the known cytoprotective function of CLU we suggest an attempt of the organism to limit further muscle damage induced by myositis disease mechanisms.