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, Massimo Locati

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageBritish English
Article number6499
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

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