Chronic Cholesterol Exposure Disrupts Macrophage Polarization and Cytokine Secretion in a 3D Microenvironment
Year: 2026
Type: article
Abstract: Cholesterol is essential for membrane organization and signaling, but excess cholesterol is increasingly linked to immune dysregulation. How chronic cholesterol loading shapes macrophage differentiation and polarization remains unclear. Here, we examined the effects of sustained cholesterol exposure on THP-1 monocytes and their polarization within 3D collagen hydrogels. At the monocyte stage, cholesterol caused cytotoxicity above 3 mg/mL, with an early decline in reactive oxygen species and metabolic remodeling marked by cholesterol accumulation, tricarboxylic acid cycle suppression, and redox imbalance. Subcytotoxic doses preserved cell count but altered metabolic profiles, indicating a primed state. Differentiation into uncommitted M0 macrophages produced only minimal phenotypic changes, though modest increases in IL-10, IFN-γ, and IP-10 suggested early functional effects. Under M1 polarization, cholesterol-loading macrophages showed reduced expression of CD80, CD86, and HLA-DR, yet secreted higher levels of both pro-inflammatory (IL-12p70, IFN-γ, IL-17A, MCP-1, IL-2) and regulatory (IL-10, IL-4) cytokines. Under M2 polarization, canonical markers CD206, CD105, and CD163 were diminished, while secretion of TGF-β1, IL-10, TNF-α, and IL-12p70 was increased. Across both conditions, cholesterol consistently uncoupled surface phenotype from cytokine output, producing a noncanonical hypersecretory state. These findings suggest that cholesterol primes monocytes and disrupts macrophage polarization, redirecting them toward mixed, hypersecretory phenotypes independent of stimulus. This work links cholesterol-induced metabolic stress to altered macrophage plasticity, with implications for maladaptive immune responses in cholesterol-rich environments.
Source: ACS Omega
Authors: Aliyaa Ali Alzaabi, Dheyab Saleh Abubaker, Jiranuwat Sapudom, Yamanappa Hunashal, Fabio Piano, Jeremy Teo
Institutions: New York University Abu Dhabi, New York University
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,935
Funder: New York University Abu Dhabi
Award: G1516813628
OpenAlex ID: W7127949017