[HTML][HTML] A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis
A Takezaki, S Tsukumo, Y Setoguchi… - Journal of Experimental …, 2019 - rupress.org
Journal of Experimental Medicine, 2019•rupress.org
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 …
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 …
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.
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