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bioRxiv · 10.1101/2020.05.06.080481

Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway

Deerhake, M. E.·Danzaki, K.·Inoue, M.·Cardakli, E. D.·Nonaka, T.·Aggarwal, N.·Barclay, W. E.·Ji, R. R.·Shinohara, M. L.
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Abstract

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 AbstractO_LIDectin-1 is a protective C-type lectin receptor (CLR) in experimental autoimmune encephalomyelitis (EAE) C_LIO_LIDectin-1 promotes expression of Osm, a neuroprotective IL-6 family cytokine, in myeloid cells C_LIO_LIOsmR signaling in astrocytes limits EAE progression and promotes remission C_LIO_LINon-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 C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/080481v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@885aa2org.highwire.dtl.DTLVardef@1f68087org.highwire.dtl.DTLVardef@70263aorg.highwire.dtl.DTLVardef@ddc3b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Deerhake, M. E., Danzaki, K., Inoue, M., Cardakli, E. D., Nonaka, T., Aggarwal, N., Barclay, W. E., Ji, R. R., Shinohara, M. L.. 2020-05-08. Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway. https://doi.org/10.1101/2020.05.06.080481

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