RT Journal Article
SR Electronic
T1 Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.06.080481
DO 10.1101/2020.05.06.080481
A1 Deerhake, M. Elizabeth
A1 Danzaki, Keiko
A1 Inoue, Makoto
A1 Cardakli, Emre D.
A1 Nonaka, Toshiaki
A1 Aggarwal, Nupur
A1 Barclay, William E.
A1 Ji, Ru Rong
A1 Shinohara, Mari L.
YR 2020
UL http://biorxiv.org/content/early/2020/05/08/2020.05.06.080481.abstract
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.