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

M. Elizabeth Deerhake, Keiko Danzaki, Makoto Inoue, Emre D. Cardakli, Toshiaki Nonaka, Nupur Aggarwal, William E. Barclay, Ru Rong Ji, Mari L. Shinohara

Preprint posted on 8 May 2020

Dectin-1 mediates the induction of an unexpected anti-inflammatory program in myeloid cells and limits neuroinflammation

Selected by Pedro Papotto

Categories: immunology


Different immune cells employ discrete receptors and strategies to sense their surroundings: lymphocytes – the prototypical cell type from the adaptive immune system – possess rearranged antigen receptors, giving these cells the ability to mount antigen-specific responses; on the other hand, leukocytes from the innate immune system employ a myriad of pattern recognition receptors (PRRs), which recognize both microbial-associated molecular patterns (MAMPs) and host-derived danger-associated molecular patterns (DAMPs), to initiate more broad immune responses. For a long time, immunologists have been trying to find the missing links between environmental signals and the development of autoimmune diseases. However, given their capacity to specifically target self-antigens, lymphocytes (and their interactions with the environment) have been one of the major focus of autoimmunity research. Thus, less is known about the role of PRRs in the pathogenesis of autoimmune diseases. Here in this preprint, Deerhake and colleagues show that engagement of the PRR Dectin-1 induces an unexpected protective transcriptional program in innate immune cells ameliorating the course of experimental autoimmune encephalomyelitis (EAE), the main mouse model for multiple sclerosis (MS).

Key Findings

The C-type lectin receptor Dectin-1 is protective in EAE by limiting leukocyte migration to the CNS.

By analysing the expression of PRRs in published MS brain lesion datasets, the authors found that, when compared to control groups, MS patients have increased brain expression of CLEC7A (the gene encoding for Dectin-1). In order to investigate a possible role for Dectin-1 in CNS inflammation, the authors employed the well characterized EAE model. Surprisingly, Clec7a knockout (KO) mice presented a more severe disease and increased number of CNS-infiltrating leukocytes when compared to their wild-type (WT) counterparts. In a mixed bone marrow chimera (BMC) setting, similar fractions of Clec7a KO and WT cells were shown to infiltrate the CNS during EAE, suggesting that Dectin-1 expression is not required for CNS entry. Altogether, these results indicate that Dectin-1 regulates leukocyte CNS migration in a cell-extrinsic manner, thus limiting inflammation.

Dectin-1 signalling in myeloid cells promotes the expression of Osm.

Profiling of different immune cell populations showed that both in steady-state and upon inflammation Dectin-1 is expressed by myeloid cells, such as monocytes and neutrophils, but not by T and B lymphocytes. During EAE, microglia also upregulate Dectin-1 expression, albeit to a lesser extent than CNS-infiltrating myeloid cells. However, as microglia are mostly radioresistant, generation of BMCs by transplanting Clec7a KO cells into a WT host and vice-versa strongly suggested that Dectin-1 expression on infiltrating myeloid cells is critical to mediate Dectin-1 protective effects. In vitro stimulation of myeloid cells from both naïve or EAE-induced mice with the Dectin-1 agonist curdlan induced the expression of Osm, the gene encoding for Oncostatin M (Osm) – a cytokine with known neuroprotective functions. Interestingly, in situ mRNA hybridization showed that Osm was upregulated in CD11b+ myeloid cells from the spinal cord after EAE induction, and this was decreased in Clec7a KO mice. Taken together, these results show that CNS-infiltrating myeloid cells are the main subset of Dectin-1- expressing cells during the course of EAE; and upon Dectin-1 activation, these cells respond by producing Osm.

Osm production in myeloid cells derives from Card9-independent Dectin-1 signalling.

Interestingly, using mice deficient for Card9 (one of the main adaptors of Dectin-1 signalling pathway) the authors observed a decrease in EAE severity. By employing RNA sequencing and qPCR in Card9 KO or WT myeloid cells treated with curdlan the authors found two discrete transcriptional profiles donwstream Dectin-1 activation: Card9-dependent gene signature is enriched in pro-inflammatory genes, whereas Card9-independent signalling leads to the expression of genes with neuroprotective functions, including Osm, in an NFAT-dependent fashion. Therefore, apart from its well-studied pro- inflammatory function, Dectin-1 signalling can also induce a transcriptional program enriched for negative regulators of inflammation and tissue protective genes.

Oncostatin M receptor (OsmR) ablation in astrocytes results in less severe late-stage EAE.

OsmR has been shown to mediate the neuroprotective functions of Osm in different models. In accordance with the literature, the authors also found OsmR expression to be restricted to astrocytes and axons, but not leukocytes. Thus, the authors generated mice deficient for OsmR specifically in astrocytes. As expected, OsmR ablation increased disease severity and impaired remission; even though these differences were only observed during the late-stage of the disease.


In this study, Deerhake and colleagues show that Dectin-1 – a PRR well known for its ability to induce IL-1β production (a key molecule in the pathogenesis of many autoimmune diseases) – is, in fact, protective in a CNS autoimmunity setting. Furthermore, the authors provide substantial data showing that Dectin-1 is able to induce a transcriptional program enriched in genes for negative regulation of inflammation and tissue protective responses in myeloid cells, in addition to the classical pro-inflammatory program well described during fungal infections. Among the different proteins upregulated during Dectin-1 activation, Oncostatin M might be mediating the observed effects of Dectin-1 in their mouse model of CNS auto-inflammation. Overall, this work raises many interesting questions regarding the role of PRRs in auto-inflammation andopens up exciting opportunities for translational approaches in neuro-immune disorders.

Open Questions

  • The decrease in EAE severity observed in Clec7a KO mice seems to stem from the increased leukocyte infiltration in the CNS during the early stages of the As it seems rather early for Osm functions in neuronal survival and in the remyelination process be relevant, how could Osm be mediating this process?
  • OsmR ablation leads to differences in the late-stages of EAE pathogenesis, arguing that OsmR+ astrocytes are important only in the recovery phase. However, Clec7a KO mice display differences very early on. Could Dectin-1 and/or Osm be acting outside the CNS in the early stages of EAE to control leukocyte migration into CNS?
  • Also, does Osm administration rescues the phenotype observed in Clec7a KOmice?
  • In the case of EAE, what could be the ligands for Dectin-1 mediating its neuroprotective roles?
  • It is fascinating that the same receptor can induce two transcriptional programs so distinct from each other. What determines the fate of the downstream signalling after Dectin-1 engagement?

Tags: central nervous system, innate immunity, multiple sclerosis, neuroinflammation, pattern recognition receptor

Posted on: 10 June 2020


Read preprint (No Ratings Yet)

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here