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Ancestry-Linked IL-10 Signaling and Macrophage Activation Modulate Fibroblast Responses to Oxidative Stress in a PEG-Based Microphysiological System

ABSTRACT: Fibroblast responses to injury are shaped by cytokine signaling and macrophage activation, yet the extent to which these pathways vary across individuals, and how ancestry-associated immune differences influence fibrosis risk, remains poorly understood. Here, we developed a poly(ethylene glycol) (PEG)-based hydrogel microphysiological system to model fibroblast–macrophage interactions following oxidative stress and integrate donor-specific immune signals using matched macrophages and serum. Circulating monocytes from individuals of self-reported African American ancestry exhibited higher expression of CCL4 and increased serum IL-10, whereas those from European ancestry donors showed elevated OXER1 expression. Within the hydrogel, oxidative stress reduced fibroblast number while inducing Ki67 and p16. Exogenous TGF-β1 enhanced fibroblast survival and collagen 3 production but did not independently increase α-smooth muscle actin (α-SMA). Anti-inflammatory macrophages promoted fibroblast activation through mechanisms resistant to TGF-β receptor inhibition. Incorporating donor-derived macrophages and serum revealed that cultures from individuals of European ancestry demonstrated higher fibroblast α-SMA and p16 expression, despite lower systemic IL-10 levels. Pharmacologic inhibition of IL-10 further increased α-SMA, particularly in European 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313951 | GEO | 2025/12/23

REPOSITORIES: GEO

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Ancestry-Linked IL-10 Signaling and Macrophage Activation Modulate Fibroblast Responses to Oxidative Stress in a PEG-Based Microphysiological System

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