2025-12-08 イェール大学
<関連情報>
- https://medicine.yale.edu/internal-medicine/news-article/new-study-reveals-key-signaling-pathway-in-pulmonary-fibrosis/
- https://www.science.org/doi/10.1126/scitranslmed.adr2277
調節不全の肺胞2型上皮細胞タンパク質恒常性は線維性マクロファージ遊走阻止因子-CD74シグナル伝達を促進する Dysregulated alveolar type 2 epithelial cell proteostasis promotes fibrogenic macrophage migration inhibitory factor–CD74 signaling
Sang-Hun Kim, Jessica Nouws, Jannik Ruwisch, Gavitt A. Woodard, […] , and Maor Sauler
Science Translational Medicine Published:3 Dec 2025
DOI:https://doi.org/10.1126/scitranslmed.adr2277
Editor’s summary
Idiopathic pulmonary fibrosis (IPF) involves alveolar type 2 epithelial cells (AEC2s), but how these cells contribute to disease or recovery is not fully mechanistically understood. Kim et al. used aging and genetic mouse models to better understand the ubiquitin-proteasome system (UPS) in this context. Deletion of the cullin 3 gene in AEC2s to model UPS impairment caused fibrosis on its own and exacerbated experimental fibrosis in mice. This also increased macrophage migration inhibitory factor (MIF) proteins, which when inhibited in AEC2s attenuated fibrosis in the mouse model. Pharmacological inhibition of MIFs attenuated fibrosis in two different mouse models of IPF, as well as in precision-cut human lung slices treated with a fibrotic cocktail. In patients with IPF, the MIF amount in bronchoalveolar lavage fluid was elevated compared with that in healthy individuals and was associated with increased mortality. Together, these data demonstrate epithelial-macrophage signaling that may be a potential therapeutic target for IPF. —Brandon Berry
Abstract
Aberrant proteostasis in alveolar type 2 epithelial cells (AEC2s) contributes to idiopathic pulmonary fibrosis (IPF), but the role of the ubiquitin-proteasome system (UPS) is unclear. Here, we show that UPS disruption in AEC2s amplifies profibrotic signaling to macrophages through macrophage migration inhibitory factor (MIF) family proteins in several models. Modeling UPS disruption with an AEC2-specific cullin 3 (Cul3) deletion produced spontaneous fibrosis in a physiological aging mouse model and exacerbated fibrosis in the bleomycin-induced lung injury model. This was accompanied by expansion of transitional epithelial states and increased MIF and MIF-2 in lung tissue and bronchoalveolar lavage fluid (BALF) in the model. Global or conditional AEC2-specific deletions of Mif or Mif-2 attenuated fibrosis in the bleomycin-treated mouse model, as did conditional deletions of Cd74, the cognate receptor for MIF and MIF-2, in C-X3-C motif chemokine receptor 1 (Cx3cr1)–expressing and platelet factor 4 (Pf4)–expressing cells. Pharmacological inhibition of MIF attenuated fibrosis in bleomycin-treated and transforming growth factor–β1 (TGFB1) transgenic mouse models and in ex vivo human precision-cut lung slices treated with fibrotic cocktail. In study participants with IPF, BALF MIF was elevated compared with that in study participants without IPF. In participants with IPF, BALF MIF greater than 4000 picograms per milliliter was associated with increased mortality compared with participants with IPF with lower MIF. Together, these findings define a UPS-sensitive epithelial-macrophage signaling connection and identify MIF-CD74 cross-talk as a potential therapeutic target in fibrotic lung disease.
