Pathologic roles of innate immunity in neurologic disorders are well described, but their beneficial aspects are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. Here, we report that Dectin-1 limited experimental autoimmune encephalomyelitis (EAE), while its downstream signaling molecule, Card9, promoted the disease. Myeloid cells mediated the pro-resolution function of Dectin-1 in EAE with enhanced gene expression of the neuroprotective molecule, Oncostatin M (Osm), through a Card9-independent pathway, mediated by the transcription factor NFAT. Furthermore, we find that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. Notably, Dectin-1 did not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Instead, endogenous Dectin-1 ligands, including galectin-9, in the central nervous system (CNS) were involved to limit EAE. Our study reveals a mechanism of beneficial myeloid cell-astrocyte crosstalk regulated by a Dectin-1 pathway and identifies potential therapeutic targets for autoimmune neuroinflammation.

先天免疫在神经系统疾病中的病理作用已得到很好的描述，但其有益方面却知之甚少。Dectin-1 是一种 C 型凝集素受体 (CLR)，众所周知会诱发炎症。在此，我们报告 Dectin-1 限制了实验性自身免疫性脑脊髓炎 (EAE)，而其下游信号分子 Card9 则促进了这种疾病。髓样细胞在 EAE 中介导 Dectin-1 的促消退功能，并通过转录因子 NFAT 介导的独立于 Card9 的途径，增强神经保护分子制瘤素 M (Osm) 的基因表达。此外，我们发现 Osm 受体 (OsmR) 在星形胶质细胞中特异性发挥作用，可降低 EAE 的严重程度。值得注意的是，Dectin-1 对热灭活的分枝杆菌没有反应，诱导EAE的佐剂。相反，中枢神经系统 (CNS) 中的内源性 Dectin-1 配体（包括半乳糖凝集素 9）参与限制 EAE。我们的研究揭示了由 Dectin-1 通路调节的有益骨髓细胞-星形胶质细胞串扰的机制，并确定了自身免疫性神经炎症的潜在治疗靶点。