Anti-IL-33 monoclonal antibody attenuates MAILD by suppressing the PI3K/AKT/mTOR signal pathway

Interstitial lung disease (ILD) is a serious complication of idiopathic inflammatory myopathies (IIM) for which targeted therapies are lacking. Our previous work identified interleukin‑33 (IL‑33) as playing a key role in the pathogenesis of IIM-ILD.

Using a mouse model of myositis-associated ILD (MAILD), including IL‑33 knockout (IL‑33 KO) mice, together with clinical samples, proteomics and multiple cellular reporter systems (dual luciferase, mTOR nuclear translocation reporter), we assessed the effects of IL‑33 NAb on lung injury repair, macrophage polarisation and endothelial/epithelial protection.

IL‑33 NAb significantly reduced pulmonary inflammation and collagen deposition, improved body weight, and ameliorated liver and muscle biochemical parameters in MAILD mice. Notably, IL‑33 KO MAILD mice exhibited almost identical phenotypic improvements to the IL‑33 NAb‑treated group, confirming IL‑33 as a core driver of the disease. Mechanistically, IL‑33 NAb blocked aberrant NETs deposition, reduced PI3K/AKT/mTOR phosphorylation, and suppressed NF‑κB and STAT3 activation. Consequently, it inhibited both pro‑inflammatory M1 and pro‑fibrotic M2 macrophage polarisation, alleviated alveolar epithelial‑mesenchymal transition (EMT), preserved endothelial CD31 expression, and enhanced tissue repair via cytoskeletal remodelling.

IL‑33 NAb exerts significant anti‑inflammatory and anti‑fibrotic effects through multi‑target interventions. Both genetic (IL‑33 KO) and pharmacological (IL‑33 NAb) evidence demonstrate that IL‑33 is a key driver of IIM-ILD, acting via PI3K/AKT/mTOR‑mediated NF‑κB/STAT3 activation. This provides a novel therapeutic strategy for IIM-ILD.