{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:11:43Z","timestamp":1780791103201,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI020\/00923"],"award-info":[{"award-number":["PI020\/00923"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI024\/00978"],"award-info":[{"award-number":["PI024\/00978"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) has been implicated in vascular inflammation beyond its action on LDL-C degradation. We investigated whether PCSK9 may exacerbate proinflammatory signaling of M1 macrophages and if its neutralization with alirocumab could attenuate this effect and plaque progression by LDL-C independent mechanisms. Methods: ApoE\u2212\/\u2212 mice were treated with alirocumab for 13 weeks, and aortic arches were isolated for atherosclerotic plaque characterization based on lesion size and lipid and macrophage infiltration. Plasma and splenic monocytes\/macrophages were also assessed by flow cytometry, and PCSK9, the lipid profile, and inflammatory cytokines were measured by qPCR or Western blot. Cultured THP-1-derived M1 macrophages were stimulated with PCSK9 and evaluated for TLR4-NF\u03baB-NLRP3 activation and cytokine production. In addition, soluble PCSK9, LDL-C, and proinflammatory factors were analyzed in 1190 patients with acute coronary syndrome (ACS). Results: Alirocumab reduced plaque lesion (0.42-fold; p &lt; 0.05) and lipid (0.63-fold; p &lt; 0.01) and macrophage (0.61-fold; p &lt; 0.05) infiltration, mainly the M1 subtype (0.37-fold; p &lt; 0.01), as well as TLR4, NLRP3 and caspase-1 expressions (0.49-fold, 0.51-fold and 0.51-fold, respectively; p &lt; 0.05), without altering LDL-C. Also, it decreased proinflammatory cytokines but enhanced anti-inflammatory factors and M2 markers at the descending aorta. Alirocumab enriched circulating Ly6Clow monocytes (1.51-fold; p &lt; 0.05) and splenic M2 macrophages (1.32-fold; p &lt; 0.01), while reducing M1 (0.62-fold; p &lt; 0.05). In cultured M1 macrophages, PCSK9 overexpressed proinflammatory cytokines (i.e., CXCL9, CXCL10, TNF-\u03b1, IL-1\u03b2, and IL-6), downregulated anti-inflammatory mediators (i.e., CCL17, TGM2, TGF-\u03b21, and IL-10), and promoted NF\u03baB-p65 nuclear translocation and NLRP3 and gasdermin-D activation. However, TLR4 inhibition or silencing blunted these effects. In patients with AC, there was a positive association between PCSK9 and hsCRP and FGF-23 plasma levels, independently of LDL-C. Conclusions: PCSK9 may be released in parallel to proinflammatory factors such as hsCRP and FGF-23 in patients with ACS, independently of LDL-C levels. PCSK9 may directly promote macrophage-driven inflammatory responses through the TLR4-NF\u03baB-NLRP3 signaling, but its neutralization with alirocumab attenuated this inflammatory axis and limited atherosclerotic progression, supporting an anti-inflammatory benefit secondary to PCSK9 inhibition.<\/jats:p>","DOI":"10.3390\/biom16030397","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T14:43:07Z","timestamp":1772808187000},"page":"397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Alirocumab Attenuated Plaque Inflammation and PCSK9-Induced Proinflammatory Signalling in M1 Macrophages Independently of Lipid Lowering"],"prefix":"10.3390","volume":"16","author":[{"given":"Cristina","family":"Espadas","sequence":"first","affiliation":[{"name":"Laboratory of Vascular Pathology and Diabetes, Fundaci\u00f3n Instituto de Investigaciones Sanitarias-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Soto-Catal\u00e1n","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology and Diabetes, Fundaci\u00f3n Instituto de Investigaciones Sanitarias-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9639-2281","authenticated-orcid":false,"given":"Mar\u00eda","family":"Romero-Cote","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology and Diabetes, Fundaci\u00f3n Instituto de Investigaciones Sanitarias-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Kavanagh","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology and Diabetes, Fundaci\u00f3n Instituto de Investigaciones Sanitarias-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5084-2349","authenticated-orcid":false,"given":"Isabel","family":"Herrero-Del Real","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology and Diabetes, Fundaci\u00f3n Instituto de Investigaciones Sanitarias-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1426-6194","authenticated-orcid":false,"given":"Adriana","family":"Ortega-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Biology and Microbiota, Instituto de Investigaciones Sanitarias Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3458-0328","authenticated-orcid":false,"given":"Jairo","family":"Lumpuy-Castillo","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology and Diabetes, Fundaci\u00f3n Instituto de Investigaciones Sanitarias-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5056-6489","authenticated-orcid":false,"given":"Dulcenombre","family":"G\u00f3mez-Garre","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Biology and Microbiota, Instituto de Investigaciones Sanitarias Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6321-2666","authenticated-orcid":false,"given":"Jes\u00fas","family":"Egido","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology and Diabetes, Fundaci\u00f3n Instituto de Investigaciones Sanitarias-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28029 Madrid, 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