Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation fl ammation

초록

Background Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial. Methods Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD. Findings Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment. Interpretation These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor.

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