Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammationResearch in context
Sung Hae Chang,
Seyoung Jung,
Jeong Jun Chae,
Jeong Yeon Kim,
Seon Uk Kim,
Ji Yong Choi,
Hye-Jeong Han,
Hyun Taek Kim,
Hak-Jae Kim,
Hyun Je Kim,
Woong Yang Park,
Jeffrey A. Sparks,
Eun Young Lee,
Jeong Seok Lee
Affiliations
Sung Hae Chang
Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, 31151, South Korea
Seyoung Jung
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
Jeong Jun Chae
Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea
Jeong Yeon Kim
Inocras, Inc., San Diego, CA, 92121, USA; Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
Seon Uk Kim
Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
Ji Yong Choi
Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
Hye-Jeong Han
Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
Hyun Taek Kim
Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
Hak-Jae Kim
Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
Hyun Je Kim
Department of Biomedical Science, Seoul National University, Seoul, 03080, Republic of Korea
Woong Yang Park
Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
Jeffrey A. Sparks
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Eun Young Lee
Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Corresponding author.
Jeong Seok Lee
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea; Inocras, Inc., San Diego, CA, 92121, USA; Corresponding author. Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, Republic of Korea.
Summary: 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. Funding: This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.
