{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T21:44:23Z","timestamp":1763415863686,"version":"3.41.2"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). In MS, CNS-infiltrating monocytes differentiate to tissue resident macrophages which are found in large numbers within the injured areas of the brain where they play a central role in driving disease progression through demyelination and tissue destruction. However, infiltrating monocytes and their derivative macrophages can also serve protective functions. In this study we investigated a possible role of intrathecal mononuclear phagocytes (infiltrating monocytes and macrophages) expressing dual immunoglobulin domain-containing cell adhesion molecule (DICAM) in neuroinflammation. Compared to symptomatic controls (n = 14), treatment-na\u00efve patients with relapsing-remitting MS (n = 21) had a reduced prevalence of DICAM<jats:sup>+<\/jats:sup> mononuclear phagocytes in CSF. When patients were treated with natalizumab (n = 12), an antibody blocking migration of blood leukocytes to the CNS, we observed that DICAM<jats:sup>+<\/jats:sup> monocytes were still recruited to the CSF and that the level of soluble DICAM (sDICAM) in CSF was significantly increased in natalizumab-treated patients (n = 42) compared to untreated patients (n = 43). sDICAM and the prevalence of DICAM<jats:sup>+<\/jats:sup> mononuclear phagocytes in CSF furthermore correlated negatively with concentrations of various cytokines, including TNF\u03b1. Analysing the functional properties of DICAM showed that LPS-induced TNF\u03b1-production in mononuclear phagocytes was effectively reduced by signalling through surface-bound DICAM. This discovery, together with the observation of a high prevalence of infiltrating DICAM<jats:sup>+<\/jats:sup> mononuclear phagocytes in individuals with no disease or in which disease was kept under control, suggests an immunomodulatory role of DICAM<jats:sup>+<\/jats:sup> mononuclear phagocytes. DICAM has been shown to engage in homophilic interactions with DICAM expressed on the same cell. If sDICAM in a similar way can engage with DICAM on adjacent cells, the increased intrathecal sDICAM of natalizumab-treated patients may help regulate inflammation in a paracrine way. Overall, our data suggest that DICAM<jats:sup>+<\/jats:sup> mononuclear phagocytes play a role in controlling neuroinflammation.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1628398","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T05:31:41Z","timestamp":1753680701000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A role for DICAM+ mononuclear phagocytes in controlling neuroinflammation in multiple sclerosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Marina Rode","family":"von Essen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie Mathilde","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sahla","family":"El Mahdaoui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria 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