Phospho-MLKL Upregulation in Immune-Mediated Necrotizing Myopathy: Implications for Disease Pathophysiology and...

Immune-mediated necrotizing myopathy (IMNM) is a subtype of idiopathic inflammatory myopathies (IIMs) characterized by severe muscle weakness and refractory response to immunotherapy. Recent studies proposed a role for necroptosis in IMNM-associated myonecrosis. This study aims to investigate the potential diagnostic value of phospho-mixed lineage kinase domain-like protein (pMLKL), the executive molecule of necroptosis, for IMNM. Sero-positive and -negative IMNM patients and various myopathies with myonecrosis diagnosed in Huashan Hospital during October 2020 to October 2022 were enrolled in this study. Comprehensive immunohistochemical staining including pMLKL was performed. The spatial distribution of pMLKL was assessed by qualitative and semi-quantitative scoring. Upregulation of pMLKL on sarcolemma was seen in both IIMs and non-IIMs (nIIMs) with distinct spatial patterns and varying positive rates. In IMNM and nIIM, it radiates outward from the center of myonecrosis and is upregulated on the surrounding non-necrotic myofibers, while in dermatomyositis, it is extensively upregulated around microinfarcts but not expressed within them. IMNM patients showed a 93.48% pMLKL expression rate, surpassing other IIMs (50%) and nIIMs (47.9%) (p < 0.0001). The concurrent upregulation and colocalization of pMLKL, MHC-I, and MAC on non-necrotic myofibers lack consistency. The frequent upregulation of pMLKL in IMNM suggests a potential correlation between necroptosis and the etiology as well as progression of IMNM. Nevertheless, its upregulated expression across diverse myopathic conditions attenuates its efficacy as a diagnostic myopathological biomarker for IMNM.