von Essen Marina Rode, Hansen Marie Mathilde, El Mahdaoui Sahla, Hvalkof Victoria Hyslop, Hansen Malene Bredahl, Buhelt Sophie, Sellebjerg Finn
Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Front Immunol. 2025 Jul 28;16:1628398. doi: 10.3389/fimmu.2025.1628398. eCollection 2025.
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.
多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性疾病。在MS中，浸润中枢神经系统的单核细胞分化为组织驻留巨噬细胞，这些巨噬细胞大量存在于脑损伤区域，它们通过脱髓鞘和组织破坏在推动疾病进展中起核心作用。然而，浸润的单核细胞及其衍生的巨噬细胞也可发挥保护功能。在本研究中，我们调查了表达双免疫球蛋白结构域细胞粘附分子（DICAM）的鞘内单核吞噬细胞（浸润的单核细胞和巨噬细胞）在神经炎症中的可能作用。与有症状的对照组（n = 14）相比，未经治疗的复发缓解型MS患者（n = 21）脑脊液中DICAM单核吞噬细胞的患病率降低。当患者接受那他珠单抗治疗时（n = 12），那他珠单抗是一种阻断血液白细胞向中枢神经系统迁移的抗体，我们观察到DICAM单核细胞仍被募集到脑脊液中，并且与未治疗的患者（n = 43）相比，那他珠单抗治疗的患者（n = 42）脑脊液中可溶性DICAM（sDICAM）水平显著升高。此外，脑脊液中sDICAM和DICAM单核吞噬细胞的患病率与包括TNFα在内的各种细胞因子的浓度呈负相关。分析DICAM的功能特性表明，通过表面结合的DICAM发出信号可有效降低单核吞噬细胞中LPS诱导的TNFα产生。这一发现，连同在无疾病或疾病得到控制的个体中观察到浸润的DICAM单核吞噬细胞的高患病率，提示DICAM单核吞噬细胞具有免疫调节作用。已证明DICAM可与同一细胞上表达的DICAM进行同源性相互作用。如果sDICAM能以类似方式与相邻细胞上的DICAM结合，那他珠单抗治疗患者鞘内sDICAM的增加可能有助于以旁分泌方式调节炎症。总体而言，我们的数据表明DICAM单核吞噬细胞在控制神经炎症中起作用。
