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The hyperlipoproteinemia triggers a series of cellular changes, particularly the activation of the macrophages, which play a crucial role in the development and progression of atherosclerosis. The presence of free cholesterol (FC) in lipoproteins may contribute to macrophage stimulation. However, the mechanisms linking the accumulation of FC in macrophages to their pro\u2010inflammatory activation remain poorly understood. Our research found a positive correlation between the number of pro\u2010inflammatory macrophages (CD14\u2009+\u2009CD16\u2009+\u2009CD36<jats:sup>high<\/jats:sup>) in visceral adipose tissue and the levels of LDL\u2010C and cholesterol remnant particles in 56 healthy people. In contrast, the proportion of anti\u2010inflammatory, alternatively activated macrophages (CD14\u2009+\u2009CD16\u2010CD163+) correlated negatively with HDL\u2010C. Additionally, our in\u00a0vitro study demonstrated that macrophages accumulating FC promoted a pro\u2010inflammatory response, activating the <jats:italic>TNF\u2010\u03b1<\/jats:italic> and chemokine <jats:italic>CCL3<\/jats:italic> genes. Furthermore, the accumulation of FC in macrophages alters the surface receptors on macrophages (CD206 and CD16) and increases cellular granularity. Notably, the CD36 surface receptor and the <jats:italic>ACAT<\/jats:italic> and <jats:italic>CD36<\/jats:italic> genes did not show a response. These results suggest a link between excessive FC accumulation and systemic inflammation to underlie the development of atherosclerosis.<\/jats:p>","DOI":"10.14814\/phy2.70367","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T02:26:42Z","timestamp":1747967202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Human macrophage pro\u2010inflammatory polarization in response to free cholesterol and cholesterol remnants"],"prefix":"10.14814","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0150-0667","authenticated-orcid":false,"given":"Karel","family":"Paukner","sequence":"first","affiliation":[{"name":"Laboratory for Atherosclerosis Research Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine  Prague Czech Republic"},{"name":"Department of Physiology, Faculty of Science Charles University  Prague Czech 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