{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:30:44Z","timestamp":1789475444191,"version":"build-2803163510"},"reference-count":114,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, immune cells, and fibrotic tissue within the arterial wall. Among the immune cells that drive this process, macrophages play a central role by mediating both inflammatory activation and tissue repair. Their polarization into either pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes determines whether plaque progression or stabilization occurs. S100 proteins, particularly S100A8, S100A9, and S100A12, are critical regulators of macrophage function in atherosclerosis. Acting as damage-associated molecular patterns, these calcium-binding proteins interact with receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR)-4 to sustain inflammatory signaling, promote oxidative stress, and amplify cytokine production within atherosclerotic plaques. Elevated S100 protein levels correlate with increased macrophage infiltration, plaque instability, and heightened cardiovascular risk. Understanding how S100 proteins influence macrophage polarization offers new insights into the mechanisms underlying chronic vascular inflammation. Targeting the S100A8\/A9 and S100A12 pathways represents a promising therapeutic strategy to mitigate macrophage-driven inflammation and improve plaque stability. Approaches such as inhibition of S100 protein-receptor interactions, suppression of downstream reactive oxygen species production, and modulation of macrophage polarization toward the M2 phenotype have shown potential in experimental models. This narrative review explores the roles of macrophages in atherosclerosis, the involvement of S100 proteins in both disease progression and macrophage polarization, and the therapeutic implications of targeting S100 protein\u2013mediated immune responses. Together, these findings highlight S100 proteins as a therapeutic target modulating macrophage polarization to attenuate atherosclerotic plaque vulnerability.<\/jats:p>","DOI":"10.3390\/biom16081115","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:09:42Z","timestamp":1785398982000},"page":"1115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["S100A8\/A9 and S100A12 Proteins and Macrophage Polarization: Therapeutic Targets in Atherosclerosis"],"prefix":"10.3390","volume":"16","author":[{"given":"Atreya J.","family":"Kulkarni","sequence":"first","affiliation":[{"name":"River Islands High School, 16601 Riptide Wy, Lathrop, CA 95330, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-2341","authenticated-orcid":false,"given":"Vikrant","family":"Rai","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1161\/CIRCRESAHA.118.313816","article-title":"Atherosclerosis: A chronic inflammatory disease with an autoimmune component","volume":"123","author":"Kobiyama","year":"2018","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Xian, X., Wang, Z., Bi, Y., Chen, Q., Han, X., Tang, D., and Chen, R. (2018). Research Progress on the Relationship between Atherosclerosis and Inflammation. 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