Authors
Sean W Cutter, Gang Liu, Eleanor Saunders, Bailey Cardwell, Vinzenz Hofferek, Thomas Soerianto, Kaitlyn Ritchie, Erin N S McGowan, Tien K Nguyen, Ivan K H Poon, Malcolm J McConville, Benjamin J Marsland, Glen P Westall, Mark D Hulett, Nicholas P Reynolds, Mark D Wright, Philip M Hansbro, Katrina J Binger
Published in
Science advances. Volume 12. Issue 29. Pages eaec8501. Jul 17, 2026. Epub Jul 15, 2026.
Abstract
Macrophages are key drivers of inflammatory and fibrotic diseases, and their activation is shaped by interactions in their tissue microenvironment. However, dissecting the processes that drive immunopathology has proved challenging, as traditional two-dimensional (2D) culture methods fail to capture the complex molecular environment that macrophages inhabit in vivo. To address this, we generated a 3D in vitro model to better mimic the in vivo biophysical microenvironment. We show that the extracellular matrix protein vitronectin promotes a previously unknown profibrotic macrophage phenotype in 3D that is characterized by increased expression of the nicotinamide adenine dinucleotide (NAD+) ectoenzyme CD38, elevated glycolysis and mitochondrial metabolism, and synthesis of the immunomodulatory metabolite itaconate. This is validated in vivo where patients with idiopathic pulmonary fibrosis have elevated vitronectin and MRC1+CD38+ macrophages, while vitronectin-deficient mice were protected from an experimental model of lung injury and fibrosis. Thus, we uncover a previously unidentified link between the composition of tissue niches and macrophage profibrotic function via altered metabolic reprogramming.
PMID:
42455923
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.
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