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

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.development. We found that non-canonical Card9-independent Dectin-1 signaling involving NFAT drives expression of Oncostatin M (Osm), an IL-6 family cytokine with neuroprotective functions 16,17,18 , and signaling through the Osm receptor (OsmR) on astrocytes reduces disease progression and promotes recovery in EAE. Furthermore, we identified a Card9-independent Dectin-1-mediated transcriptional program driving expression of Osm and other neuroprotective genes. Our findings provoke a re-consideration of Dectin-1 signaling and functions by identifying a new mechanism of protective myeloid-astrocyte communication in CNS autoimmunity. RESULTS Elevated gene expression of the C-type lectin receptor, Dectin-1 (CLEC7A) in MS lesionsWe evaluated gene expression of CLRs in multiple datasets profiling MS brain lesions 18 .Among genes encoding CLRs with known immune functions, CLEC7A (Dectin-1) and CLEC4A (DCIR), closely linked on chromosome 12, were notable for their elevated expression in MS brain specimens in two independent datasets ( Supplementary Fig. 1a-c) 19, 20, 21 , suggesting possible involvement of Dectin-1 and DCIR in MS. In EAE, DCIR has been reported to be protective 22,23 but the function of Dectin-1 in CNS autoimmunity remained unknown. Dectin-1 is a protective C-type lectin receptor in EAENext, we sought to test the function of Dectin-1 in CNS autoimmunity using EAE induced with the MOG35−55 autoantigen peptide. We initially hypothesized that Dectin-1 may exacerbate EAE severity by promoting IL-1β expression and Th17 differentiation, given its known role in antifungal immunity 3, 4 and the pathogenicity of Th17 cells in EAE development 24 . Instead, we found that Dectin-1-deficient (Clec7a -/-) mice developed more severe disease than WT mice (Fig. 1a). A mild EAE induction with a reduced amount of adjuvant also showed the protective effect of Dectin-1 (Fig. 1b). Next, we tested whether administering a Dectin-1 agonist was sufficient to limit EAE severity. To test this, we used hot alkali-depleted zymosan (d-zymosa...

Macrophages control pathological interferon responses during viral respiratory infection

“…Previous studies have described both pro-and anti-inflammatory roles for OSM (35)(36)(37). As Osm is induced in response to a variety of cues, it is possible that the tissue context of induction may shape the role of OSM.…”