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

Abstract

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.

Reconstruction of cell spatial organization from single-cell RNA sequencing data based on ligand-receptor mediated self-assembly

“…S 4 ). Since mutations or aberrant expression of SFTPA1 and TLR2 have been associated with pulmonary fibrosis, 25 , 26 the identification of the critical role of SFTPA1-TLR2 in maintaining the normal spatial organization of human alveoli by CSOmap via an unbiased approach further underscores the validity of CSOmap and the molecular insights that it may bring.…”

Contributions of alveolar epithelial cell quality control to pulmonary fibrosis

“…Deconvoluting the precise role of specific epithelial UPR pathways in lung fibrosis has been challenging. Recently, AT2-specific deletion of a key regulator of ER homeostasis, the chaperone GRP78/BiP, resulted in impaired AT2 progenitor capacity, activated TGF-β signaling, and spontaneous age-dependent fibrotic lung remodeling with features of UIP pathology (44). Perhaps no better proof of concept for the role of AT2 quality control dysfunction as a driver of lung fibrosis exists than lessons learned from mutations in surfactant proteins (SPs).…”

Genetic Risk Factors for Idiopathic Pulmonary Fibrosis: Insights into Immunopathogenesis

“…Rare variants in the two adjacent SP-A coding genes, SFTPA1 and SFTPA2, have been described in several cases of FIP. [113][114][115] While the role that these and other surfactant-related variants play in contribution to sporadic IPF remains less clear, IPF patients have been reported to have reduced BAL concentrations of SP-A compared to healthy patients, and SP-A levels are inversely correlated with survival. 116,117 Mice deficient in SP-A (SP-A −/-) show dramatically decreased bacterial clearance, impaired macrophage phagocytosis, and increased production of pro-inflammatory cytokines IL-1β, IL-6, and TNF which are also associated with fibroblast activation.…”

“…119 Additionally, it has been shown that an FIP-associated loss-of-function mutation in SFTPA1 leads to increased necroptosis in AE2 cells in mice. 113 Necroptotic cell death leads to the release of highly immunogenic intracellular proteins and has been increasingly been implicated in IPF pathogenesis. 120,121 Treatment of mice with exogenous SP-A has been shown to reduce the expression of Th2 cytokines including IL-4 and IL-5, which are involved in chronic tissue repair responses and are linked to the development of fibrosis.…”