{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:07:41Z","timestamp":1790957261116,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovative Medizinische Forschung (IMF)","award":["GO121222"],"award-info":[{"award-number":["GO121222"]}]},{"name":"Innovative Medizinische Forschung (IMF)","award":["SEED\/018\/23"],"award-info":[{"award-number":["SEED\/018\/23"]}]},{"name":"IZKF SEED","award":["GO121222"],"award-info":[{"award-number":["GO121222"]}]},{"name":"IZKF SEED","award":["SEED\/018\/23"],"award-info":[{"award-number":["SEED\/018\/23"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG), Collaborative Research Centre 656 M\u00fcnster","award":["GO121222"],"award-info":[{"award-number":["GO121222"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG), Collaborative Research Centre 656 M\u00fcnster","award":["SEED\/018\/23"],"award-info":[{"award-number":["SEED\/018\/23"]}]},{"name":"Deanery of the Medical Faculty of the Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster","award":["GO121222"],"award-info":[{"award-number":["GO121222"]}]},{"name":"Deanery of the Medical Faculty of the Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster","award":["SEED\/018\/23"],"award-info":[{"award-number":["SEED\/018\/23"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Type 2 diabetes mellitus (DM) is a major cardiovascular risk factor that induces monocyte dysfunction and contributes to their accumulation in atherosclerotic lesions. Monocyte recruitment and accumulation in the tissues contribute to chronic inflammation and are essential to the pathobiology of diabetes-induced atherosclerosis. However, the mechanisms that drive the accumulation of monocytes in the diabetic environment are not clearly understood. Methods: Primary monocytes from type 2 (T2) DM and non-T2DM individuals were isolated using magnet-assisted cell sorting. To examine the influence of a diabetic milieu on monocyte function, monocytes from T2DM patients, db\/db mice, or human monocytes subjected to hyperglycaemia were analysed for their responses to pro-atherogenic cytokines using Boyden chamber assays. Furthermore, the interactions of non-diabetic and diabetic monocytes with TNF\u03b1-inflamed endothelium were studied using live-cell imaging under physiological flow conditions. RT-qPCR and FACS were used to study the expression of relevant molecules involved in monocyte-endothelium interaction. Results: CD14+CD16\u2212 monocytes isolated from T2DM patients or monocytes exposed to hyperglycaemic conditions showed reduced chemotactic responses towards atherosclerosis-promoting cytokines, CCL2 and CX3CL1, indicating monocyte dysfunction. Under flow conditions, the transendothelial migration (TEM) capacity of T2DM monocytes was significantly reduced. Even though these monocytes adhered to the endothelial monolayer, only a few transmigrated. Interestingly, the T2DM monocytes and monocytes exposed to hyperglycaemic conditions accumulated in the ablumen following transendothelial migration. The time period in the ablumen of T2DM cells was prolonged, as there was a significant impairment of the reverse transendothelial migration (rTEM). Mechanistically, the T2DM milieu specifically induced the activation of monocyte integrins, Macrophage-1 antigen (Mac-1; integrin \u03b1M\u03b22 consisting of CD11b and CD18), and Lymphocyte function-associated antigen 1 (LFA-1; \u03b1L\u03b22 consisting of CD11a and CD18). Furthermore, elevated levels of CD18 transcripts were detected in T2DM monocytes. Junctional Adhesion Molecule 3 (JAM-3)\u2013MAC-1 interactions are known to impede rTEM and T2DM milieu-potentiated JAM-3 expression in human coronary artery endothelial cells (HCAEC). Finally, the overexpression of JAM-3 on HCAEC was sufficient to completely recapitulate the impaired rTEM phenotype. Conclusions: Our results revealed for the first time that the enhanced T2DM monocyte accumulation in the ablumen is not secondary to the elevated transmigration through the endothelium. Instead, the accumulation of monocytes is due to the direct consequence of a dysfunctional rTEM, potentially due to enhanced JAM3-MAC1 engagement. Our results highlight the importance of restoring the rTEM capacity of monocytes to reduce monocyte accumulation-dependent inflammation induction and atherogenesis in the T2DM environment.<\/jats:p>","DOI":"10.3390\/cells14191567","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T10:35:36Z","timestamp":1760006136000},"page":"1567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Type 2 Diabetes Mellitus Impairs the Reverse Transendothelial Migration Capacity (rTEM) of Inflammatory CD14+CD16\u2212 Monocytes: Novel Mechanism for Enhanced Subendothelial Monocyte Accumulation in Diabetes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4386-8533","authenticated-orcid":false,"given":"Dilvin","family":"Semo","sequence":"first","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adama","family":"Sidib\u00e9","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Centre M\u00e9dical Universitaire (CMU), Medical Faculty, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kallipatti Sanjith","family":"Shanmuganathan","sequence":"additional","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0303-7322","authenticated-orcid":false,"given":"Nicolle","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich A.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Jena, 07743 Jena, Germany"},{"name":"Practice for Endocrinology and Diabetes, MVZ Dr. Kielstein GmbH Erfurt, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6446-3990","authenticated-orcid":false,"given":"Beat A.","family":"Imhof","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Centre M\u00e9dical Universitaire (CMU), Medical Faculty, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinesh","family":"Godfrey","sequence":"additional","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"},{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Waltenberger","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), 6229 ER Maastricht, The Netherlands"},{"name":"Department of Cardiovascular Medicine, Medical Faculty, University of M\u00fcnster, 48149 M\u00fcnster, Germany"},{"name":"Hirslanden Klinik im Park, Cardiovascular Medicine, Diagnostic and Therapeutic Heart Center AG, 8002 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/S0140-6736(05)61032-X","article-title":"Type 2 diabetes: Principles of pathogenesis and therapy","volume":"365","author":"Stumvoll","year":"2005","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1001\/jama.281.14.1291","article-title":"Diabetes and decline in heart disease mortality in US adults","volume":"281","author":"Gu","year":"1999","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Diabetes Drafting Group (1985). 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