Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway
Deerhake, ME; Danzaki, K; Inoue, M; Cardakli, ED; Nonaka, T; Aggarwal, N; Barclay, WE; Ji, RR; Shinohara, ML
Pathologic 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, 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.
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