Ancestry-linked IL-10 signaling and macrophage activation modulate fibroblast responses to oxidative stress in a PEG-based microphysiological system.

Ancestry-associated immune differences influence fibrosis risk, however how fibrosis-associated pathways vary across individuals remains poorly understood. Fibroblasts are a main cell type involved in fibrosis. The fibroblast response is shaped by cytokine signaling and macrophage activation. The extent to which these pathways vary across individuals, and how ancestry-associated immune differences influence fibrosis risk, remains poorly understood. Here, a poly(ethylene glycol) (PEG)-based hydrogel microphysiological system was leveraged to model fibroblast-macrophage interactions following oxidative stress and to integrate donor-specific immune signals using matched macrophages and serum. Individuals of self-reported African ancestry exhibited higher monocyte expression of CCL4, lower monocyte expression of OXER1, and increased serum IL-10, compared to individuals of European ancestry. Within the hydrogel, oxidative stress reduced fibroblast prevalence while inducing Ki67 and p16. Exogenous TGF-β1 increased fibroblast prevalence and collagen 3 production but did not independently increase α-SMA. Incorporating donor-specific macrophages and serum revealed that cultures from individuals of European ancestry demonstrated higher fibroblast α-SMA and p16 expression. Pharmacologic inhibition of IL-10 further increased α-SMA expression, particularly in African ancestry-derived cultures, identifying IL-10 as a key protective signal limiting fibroblast activation. This hydrogel system provides a platform for dissecting inter-individual immune variation and identifying mechanisms underlying ancestry-associated fibrosis risk.