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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 IL10, whereas those from European ancestry donors showed elevated OXER1 expression. Within the hydrogel, oxidative stress reduced fibroblast number while inducing Ki67 and p16. Exogenous TGFbeta1 enhanced fibroblast survival and collagen 3 production but did not independently increase alpha smooth muscle actin (alphaSMA). Anti-inflammatory macrophages promoted fibroblast activation through mechanisms resistant to TGFbeta receptor inhibition. Incorporating donor-derived macrophages and serum revealed that cultures from individuals of European ancestry demonstrated higher fibroblast alphaSMA and p16 expression, despite lower systemic IL10 levels. Pharmacologic inhibition of IL10 further increased alphaSMA, particularly in European ancestry derived cultures, identifying IL10 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Erika Taylor Moore

PROVIDER: MSV000100385 | MassIVE | Tue Jan 06 01:07:00 GMT 2026

SECONDARY ACCESSION(S): PXD072700

REPOSITORIES: MassIVE

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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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