Dectin-1 limits CNS autoimmunity through a non-canonical pathway

Abstract

Abstract Innate immunity mediates both damage and repair of the central nervous system (CNS) in neurologic disorders. Although pathologic roles for innate immunity are well-described in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), protective aspects of the immune response are less understood. In this study, we sought to identify the function of Dectin-1, a C-type lectin receptor (CLR), in CNS autoimmunity. We found that Dectin-1 limited neuroinflammation in EAE while its canonical signaling mediator, Card9, promoted disease. Myeloid cells from the bone-marrow mediated the regulatory function of Dectin-1 in EAE and upregulated expression of Oncostatin M (Osm), a neuroprotective cytokine, through a non-canonical Card9-independent Dectin-1 signaling pathway. We found that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. RNA-seq profiling of the Card9-independent Dectin-1 transcriptional program identified multiple targets with neuroprotective functions, including Osm, which were regulated by NFAT signaling. Our data describe a new mechanism of neuroprotective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway.