Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context

Elisa Setten, Alessandra Castagna, Josué Manik Nava-Sedeño, Jonathan Weber, Roberta Carriero, Andreas Reppas, Valery Volk, Jessica Schmitz, Wilfried Gwinner, Haralampos Hatzikirou, Friedrich Feuerhake and Massimo Locati ()
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Elisa Setten: IRCCS Humanitas Research Hospital
Alessandra Castagna: IRCCS Humanitas Research Hospital
Josué Manik Nava-Sedeño: National Autonomous University of Mexico
Jonathan Weber: IRIMAS Institute, Université de Haute-Alsace
Roberta Carriero: IRCCS Humanitas Research Hospital
Andreas Reppas: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität
Valery Volk: Hannover Medical School
Jessica Schmitz: Hannover Medical School
Wilfried Gwinner: Hannover Medical School
Haralampos Hatzikirou: Khalifa University
Friedrich Feuerhake: Hannover Medical School
Massimo Locati: IRCCS Humanitas Research Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract Fibrosis is a progressive biological condition, leading to organ dysfunction in various clinical settings. Although fibroblasts and macrophages are known as key cellular players for fibrosis development, a comprehensive functional model that considers their interaction in the metabolic/immunologic context of fibrotic tissue has not been set up. Here we show, by transcriptome-based mathematical modeling in an in vitro system that represents macrophage-fibroblast interplay and reflects the functional effects of inflammation, hypoxia and the adaptive immune context, that irreversible fibrosis development is associated with specific combinations of metabolic and inflammatory cues. The in vitro signatures are in good alignment with transcriptomic profiles generated on laser captured glomeruli and cortical tubule-interstitial area, isolated from human transplanted kidneys with advanced stages of glomerulosclerosis and interstitial fibrosis/tubular atrophy, two clinically relevant conditions associated with organ failure in renal allografts. The model we describe here is validated on tissue based quantitative immune-phenotyping of biopsies from transplanted kidneys, demonstrating its feasibility. We conclude that the combination of in vitro and in silico modeling represents a powerful systems medicine approach to dissect fibrosis pathogenesis, applicable to specific pathological conditions, and develop coordinated targeted approaches.

Date: 2022
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DOI: 10.1038/s41467-022-34241-5

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