{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T21:58:21Z","timestamp":1792879101133,"version":"4.5.0"},"reference-count":122,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bingei and L & T Charitable Foundation Professorship in Dementia Research"},{"DOI":"10.13039\/501100024334","name":"State Key Laboratory of Brain and Cognitive Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100024334","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Major depressive disorder (MDD) is a multifaceted psychiatric disorder that has been a longstanding focus of research. However, its underlying mechanisms remain underexplored. Recently, the inflammatory hypothesis has gained attention, highlighting inflammation\u2019s role in MDD progression. Potential contributors to increased systemic inflammation in MDD include hyperactivation of the hypothalamic\u2013pituitary\u2013adrenal axis, dysregulation of the sympathetic nervous system, gut microbiota imbalances, the \u201cpathogen host defense\u201d hypothesis, and damage-associated molecular patterns. Traditional pathways explaining how systemic inflammation affects the central nervous system (CNS) do not fully account for the observed desynchrony between systemic and neuroinflammation in most depressed individuals. Alternative models suggest mechanisms such as reduced blood\u2013brain barrier permeability and the involvement of immune cells from the skull. This review examines the link between inflammation and MDD, focusing on systemic and neuroinflammation interactions, with special emphasis on the heterogeneity of MDD symptoms and the potential impact of dysfunction in the brain\u2019s lymphatic system. Gaining insight into the origins of inflammation in both the central nervous system and the peripheral body, along with their interactions, offers an important understanding of the inflammatory mechanisms associated with MDD for future treatment.<\/jats:p>","DOI":"10.3390\/biom15111556","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T17:06:06Z","timestamp":1762362366000},"page":"1556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Re-Examination of Inflammation in Major Depressive Disorder: Bridging Systemic and Neuroinflammatory Insights"],"prefix":"10.3390","volume":"15","author":[{"given":"Xinyu","family":"Ye","sequence":"first","affiliation":[{"name":"Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuen-Shan","family":"Ho","sequence":"additional","affiliation":[{"name":"School of Nursing, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-7993","authenticated-orcid":false,"given":"Raymond Chuen-Chung","family":"Chang","sequence":"additional","affiliation":[{"name":"Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"Malhi","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.31887\/DCNS.2002.4.1\/bbondy","article-title":"Pathophysiology of depression and mechanisms of treatment","volume":"4","author":"Brigitta","year":"2002","journal-title":"Dialogues Clin. 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