This record contains raw data related to article “Modeling the relevance of immune and metabolic cues in the macrophage/fibroblast interplay during fibrosis" Fibrosis is a progressive biological process leading to organ dysfunction in different clinical settings. As fibroblasts and macrophages are known as key cellular players for fibrosis development, we adopted an in vitro model to define the functional effects of inflammation, hypoxia, and the adaptive immune context on their functional interplay with respect to fibrosis development. Transcriptomic analysis defined the impact of each parameter, acting alone or in combination, on functional properties of both cell types, exposed individually or in a cell-cell contact. These in vitro signatures were matched with transcriptomic profiles generated on laser-captured glomeruli and cortical tubulointerstitial 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. In vitro signatures were also used to instruct the development of a mathematical model predicting the relevance of each parameter in fibrosis development scenario, which indicated tolerance to inflammatory infiltrates under otherwise favorable conditions and defined an operative window in which hypoxia exerts a crucial role, supported by the degree of inflammation. Observed signatures and model-based predictions strongly suggested that irreversible fibrosis development is the result of specific combinations of metabolic and inflammatory cues, which drive distinct profibrotic paths in the glomeruli and the tubulointerstitial compartments. These findings, which found confirmation in tissue-based quantitative immune-phenotyping of transplanted kidney biopsies, indicate that the combination of in vitro and in silico modeling represents a powerful systems medicine approach to dissect fibrosis pathogenesis and develop coordinated targeted approaches