Dectin-1 limits autoimmune neuroinflammation and promotes myeloid cell-astrocyte crosstalk via Card9-independent expression of Oncostatin M

Immunity. 2021 Mar 9;54(3):484-498.e8. doi: 10.1016/j.immuni.2021.01.004. Epub 2021 Feb 12.

Abstract

Pathologic roles of innate immunity in neurologic disorders are well described, but their beneficial aspects are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. Here, we report that Dectin-1 limited experimental autoimmune encephalomyelitis (EAE), while its downstream signaling molecule, Card9, promoted the disease. Myeloid cells mediated the pro-resolution function of Dectin-1 in EAE with enhanced gene expression of the neuroprotective molecule, Oncostatin M (Osm), through a Card9-independent pathway, mediated by the transcription factor NFAT. Furthermore, we find that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. Notably, Dectin-1 did not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Instead, endogenous Dectin-1 ligands, including galectin-9, in the central nervous system (CNS) were involved to limit EAE. Our study reveals a mechanism of beneficial myeloid cell-astrocyte crosstalk regulated by a Dectin-1 pathway and identifies potential therapeutic targets for autoimmune neuroinflammation.

Keywords: C-type lectin receptors; CLRs; Card9; Dectin-1/Clec7a; Gal-9; Galectin-9; MS; OSMR; Oncostatin M; Osm; astrocytes; innate immunity; multiple sclerosis; neuroimmunology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / immunology*
  • Brain / pathology*
  • CARD Signaling Adaptor Proteins / metabolism*
  • Cell Communication
  • Cells, Cultured
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Galectins / metabolism
  • Gene Expression Regulation
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Sclerosis / immunology*
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Myeloid Cells / immunology*
  • Neurogenic Inflammation / immunology*
  • Oncostatin M / genetics
  • Oncostatin M / metabolism
  • Oncostatin M Receptor beta Subunit / metabolism
  • Peptide Fragments / immunology
  • Receptors, Mitogen / genetics
  • Receptors, Mitogen / metabolism*
  • Signal Transduction

Substances

  • CARD Signaling Adaptor Proteins
  • CLEC9a protein, human
  • Card9 protein, mouse
  • Galectins
  • Lectins, C-Type
  • Myelin-Oligodendrocyte Glycoprotein
  • Oncostatin M Receptor beta Subunit
  • Osmr protein, mouse
  • Peptide Fragments
  • Receptors, Mitogen
  • galectin 9, mouse
  • myelin oligodendrocyte glycoprotein (35-55)
  • Oncostatin M