A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis

Akio Takezaki, Shin Ichi Tsukumo, Yasuhiro Setoguchi, Julie G. Ledford, Hisatsugu Goto, Kazuyoshi Hosomichi, Hisanori Uehara, Yasuhiko Nishioka, Koji Yasutomo

Research output: Contribution to journalArticle

1 Scopus citations


Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family. The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated up-regulation of Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice, and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK inhibitor worsened pulmonary fibrosis. These findings provide new insight into the mechanisms of IPF in which a mutation in SFTPA1 promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.

Original languageEnglish (US)
Pages (from-to)2724-2735
Number of pages12
JournalThe Journal of experimental medicine
Issue number12
Publication statusPublished - Dec 2 2019


ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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