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 (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-

• Kim, S. H.
• Nouws, J.
• Ruwisch, J.
• Woodard, G. A.
• Cooley, J.
• Khoury, J.
• Sun, H.
• Doherty, E.
• Piecychna, M.
• Manning, E. P.
• Kang, M. J.
• Bruscia, E. M.
• Wei, H.
• Zhang, Y.
• Yarovinsky, T. O.
• Hwa, J.
• Zacharias, W. J.
• Ingram, J.
• Lee, C. G.
• Elias, J. A.
• Kaminski, N.
• Redente, E. F.
• Herzog, E. L.
• Prasse, A.
• Bucala, R.
• Sauler, M.