Toxicogenomic assessment of in vitro macrophages exposed to profibrotic challenge reveals a sustained transcriptomic immune signature

• DOI: 10.1016/j.csbj.2024.10.010
• Publication Date: 2024-10-08T07:07:12Z
• Authors: Jack Morikka; Antonio Federico; Lena Möbus; Simo Inkala; Alisa Pavel; Saara Sani; Maaret Vaani; Sanna Peltola; Angela Serra; Dario Greco
• Keywords: Signature (topology); In vitro toxicology

AbstractImmune signalling is a crucial component in the progression of fibrosis. However, approaches for the safety assessment of potentially profibrotic substances, providing information on mechanistic immune responses, are underdeveloped. This study utilises a comprehensive analysis of RNA sequencing data from macrophages exposed in vitro to multiple sublethal concentrations of the profibrotic agent bleomycin, over multiple timepoints. Using a toxicogenomic framework, we performed dose-dependent analysis to filter genes truly altered by bleomycin exposure from noise and identified a subset of immune genes with a sustained dose-dependent and differential expression response to profibrotic challenge. We performed an immunoassay and revealed cytokines and proteinases responding to bleomycin exposure that closely correlate to transcriptomic alterations, underscoring the integration between transcriptional immune response and external immune signalling activity. This study not only increases our understanding of the immunological mechanisms of fibrosis, but also offers an innovative framework for the toxicological evaluation of substances with potential fibrogenic effects on macrophage signalling. Our work brings a new immunotoxicogenomic direction for hazard assessment of fibrotic compounds, through implementation of a time and resource efficient in vitro methodology.