Interleukin-33 Promotes Interstitial Lung Disease in Idiopathic Inflammatory Myopathy Via ERK-Mediated Epithelial-Mesenchymal Transition: ERK as a Potential Therapeutic Target.

Abstract

Interstitial lung disease (ILD) is the most common and prognostically severe complication of idiopathic inflammatory myopathy (IIM), for which targeted treatments remain limited. Based on previous findings that neutrophil extracellular traps (NETs) are key mediators in IIM-ILD pathogenesis and given the established role of interleukin-33 (IL-33) in promoting NETosis, we hypothesized. We integrated analyses of human IIM-ILD samples with a myositis-associated ILD (MAILD) mouse model employing IL-33 knockout (KO) and reconstitution strategies. The ERK pathway was inhibited in vivo with U0126. In vitro, IL-33 knockdown alveolar epithelial cells were challenged with NETs. Assessments included enzyme-linked immunosorbent assay, immunohistochemistry and/or immunofluorescence, Western blot, and RNA sequencing. Serum IL-33 levels were significantly elevated in patients with IIM-ILD compared with healthy controls, with concurrent upregulation of IL-33 in lung tissues. MAILD mice similarly showed increased IL-33 expression, whereas IL-33 KO mice exhibited attenuated lung inflammation, improved alveolar architecture, and decreased collagen deposition. Administration of exogenous IL-33 restored ILD severity in IL-33 KO mice to wild-type levels. The levels of p-ERK and epithelial-mesenchymal transition (EMT) markers (E-Ca and α-smooth muscle actin) correlated with IL-33 expression. U0126 reduced p-ERK levels, suppressed EMT, and ameliorated both pulmonary inflammation and fibrosis. In vitro, NETs induced EMT and ERK activation in A549 cells, effects that were abolished upon IL-33 silencing. IL-33 promotes IIM-ILD progression by activating ERK-mediate EMT, identifying the IL-33/ERK signaling axis as a potential therapeutic target. These results provide mechanistic insight into IIM-ILD pathogenesis and support translational strategies for precision intervention.