A role for DICAM+ mononuclear phagocytes in controlling neuroinflammation in multiple sclerosis
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 progr...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1628398/full |
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| Summary: | 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-naïve patients with relapsing-remitting MS (n = 21) had a reduced prevalence of DICAM+ 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+ 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+ mononuclear phagocytes in CSF furthermore correlated negatively with concentrations of various cytokines, including TNFα. Analysing the functional properties of DICAM showed that LPS-induced TNFα-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+ mononuclear phagocytes in individuals with no disease or in which disease was kept under control, suggests an immunomodulatory role of DICAM+ 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+ mononuclear phagocytes play a role in controlling neuroinflammation. |
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| ISSN: | 1664-3224 |