Dectin-1 limits autoimmune neuroinflammation and promotes myeloid cell-astrocyte crosstalk via Card9-independent expression of Oncostatin M

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. [Display omitted] •Dectin-1 limits experimental autoimmune encephalomyelitis (EAE)•Dectin-1 upregulates Osm in myeloid cells via a Card9-independent pathway•OsmR signaling in astrocytes limits EAE severity•Galectin-9 is an endogenous ligand of Dectin-1 made by astrocytes and limits EAE Pattern-recognition receptor signaling regulates neuroinflammation in an animal model of multiple sclerosis (MS). Deerhake et al. now show that Dectin-1 promotes beneficial myeloid-cell-astrocyte crosstalk in EAE by upregulating Oncostatin M through a Card9-independent pathway.