ABSTRACTPathologic roles for innate immunity in neurologic disorders are well-described, but protective aspects of the immune response are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. However, we found that Dectin-1 is protective in experimental autoimmune encephalomyelitis (EAE), while its canonical signaling mediator, Card9, promotes the disease. Notably, Dectin-1 does not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Myeloid cells mediate the protective function of Dectin-1 in EAE and upregulate gene expression of neuroprotective molecules, including Oncostatin M (Osm) through a non-canonical Card9-independent pathway, mediated by NFAT. Furthermore, we found that the Osm receptor (OsmR) functions specifically in astrocytes to reduce EAE severity. Our study revealed a new mechanism of protective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway and identifies novel therapeutic targets for CNS autoimmunity.Graphical AbstractDectin-1 is a protective C-type lectin receptor (CLR) in experimental autoimmune encephalomyelitis (EAE)Dectin-1 promotes expression of Osm, a neuroprotective IL-6 family cytokine, in myeloid cellsOsmR signaling in astrocytes limits EAE progression and promotes remissionNon-canonical Card9-independent signaling drives a distinct Dectin-1-mediated transcriptional program to induce expression of Osm and other factors with protective or anti-inflammatory functions
Exacerbation of experimental autoimmune encephalomyelitis in mice deficient for DCIR, an inhibitory C-type lectin receptor
