Dysregulated alveolar type 2 epithelial cell proteostasis promotes fibrogenic macrophage migration inhibitory factor–CD74 signaling

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 (<i>Cul3</i>) 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 <i>Mif</i> or <i>Mif-2</i> attenuated fibrosis in the bleomycin-treated mouse model, as did conditional deletions of <i>Cd74</i>, the cognate receptor for MIF and MIF-2, in C-X3-C motif chemokine receptor 1 (<i>Cx3cr1</i>)-expressing and platelet factor 4 (<i>Pf4</i>)-expressing cells. Pharmacological inhibition of MIF attenuated fibrosis in bleomycin-treated and transforming growth factor-β1 (<i>TGFB1</i>) 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.

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Publication Details

Journal
Science Translational Medicine
Published
2025-12-03
DOI
https://doi.org/10.1126/scitranslmed.adr2277
Primary Topic
Macrophage Migration Inhibitory Factor
Type
article
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article

Dysregulated alveolar type 2 epithelial cell proteostasis promotes fibrogenic macrophage migration inhibitory factor–CD74 signaling

Johad Khoury, Edward Doherty, Jennifer L. Ingram, Y. Zhang et al.
Science Translational Medicine
Macrophage Migration Inhibitory Factor
article

Dysregulated alveolar type 2 epithelial cell proteostasis promotes fibrogenic macrophage migration inhibitory factor–CD74 signaling

Johad Khoury, Edward Doherty, Jennifer L. Ingram, Y. Zhang, Maor Sauler, Marta Piecychna, Emanuela M. Bruscia, Richard Bucala, Min‐Jong Kang, Timur O. Yarovinsky, Erica L. Herzog, Gavitt A. Woodard, Antje Prasse, William J. Zacharias, Huanxing Sun, Jack A. Elias, Huanhuan Wei, Elizabeth F. Redente, John Hwa, Jessica Nouws, Chun Geun Lee, Naftali Kaminski, Edward P. Manning, Joseph Cooley, Sang‐Hun Kim, Jannik Ruwisch
article en

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 (<i>Cul3</i>) 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 <i>Mif</i> or <i>Mif-2</i> attenuated fibrosis in the bleomycin-treated mouse model, as did conditional deletions of <i>Cd74</i>, the cognate receptor for MIF and MIF-2, in C-X3-C motif chemokine receptor 1 (<i>Cx3cr1</i>)-expressing and platelet factor 4 (<i>Pf4</i>)-expressing cells. Pharmacological inhibition of MIF attenuated fibrosis in bleomycin-treated and transforming growth factor-β1 (<i>TGFB1</i>) 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.

Science Translational MedicineVol. 17(827)
Brown University (US), University Hospital of Basel (CH), National Jewish Health (US), Yale University (US), Medizinische Hochschule Hannover (DE), VA Connecticut Healthcare System (US), Fraunhofer Institute for Toxicology and Experimental Medicine (DE), Duke Medical Center (US), Duke University Hospital (US), Hanyang University (KR), University of Cincinnati Medical Center (US), University of Colorado Denver (US)
Openalex Percentile: Top 57%
Macrophage Migration Inhibitory Factor
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