PT  - JOURNAL ARTICLE
AU  - M. Elizabeth Deerhake
AU  - Keiko Danzaki
AU  - Makoto Inoue
AU  - Emre D. Cardakli
AU  - Toshiaki Nonaka
AU  - Nupur Aggarwal
AU  - William E. Barclay
AU  - Ru Rong Ji
AU  - Mari L. Shinohara
TI  - Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway
AID  - 10.1101/2020.05.06.080481
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.06.080481
4099  - http://biorxiv.org/content/early/2020/05/08/2020.05.06.080481.short
4100  - http://biorxiv.org/content/early/2020/05/08/2020.05.06.080481.full
AB  - 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 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 functionsCompeting Interest StatementThe authors have declared no competing interest.