Author Of 1 Presentation
P0954 - Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway (ID 921)
Abstract
Background
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 known to promote inflammation but its function in neuroinflammatory disorders including Multiple Sclerosis (MS) is not well characterized.
Objectives
In this study, we sought to identify the function and mechanism of Dectin-1 signaling in central nervous system (CNS) autoimmunity using an animal model of MS.
Methods
We evaluated the role of Dectin-1 signaling in experimental autoimmune encephalomyelitis (EAE) using genetically modified mouse lines, flow-cytometry analysis, and histologic evaluation. We conducted in-depth studies of Dectin-1 signaling using RNA sequencing and in vitro approaches with small molecule inhibitors.
Results
Although Dectin-1 is known to promote inflammation, we found that Dectin-1 is protective in 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, NFAT-mediated pathway. Furthermore, we found that the Osm receptor (OsmR) functions specifically in astrocytes to reduce EAE severity.
Conclusions
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.