Pathogenic Microglia Orchestrate Neurotoxic Properties of Eomes-Expressing Helper T Cells

Chenyang Zhang; Ben Raveney; Fumio Takahashi; Tzu-Wen Yeh; Hirohiko Hohjoh; Takashi Yamamura; Shinji Oki

doi:10.3390/cells12060868

Pathogenic Microglia Orchestrate Neurotoxic Properties of Eomes-Expressing Helper T Cells

Cells. 2023 Mar 10;12(6):868. doi: 10.3390/cells12060868.

Authors

Chenyang Zhang^{1

2}, Ben Raveney¹, Fumio Takahashi¹, Tzu-Wen Yeh¹, Hirohiko Hohjoh³, Takashi Yamamura¹, Shinji Oki¹

Affiliations

¹ Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
² Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
³ Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.

Abstract

In addition to disease-associated microglia (DAM), microglia with MHC-II and/or IFN-I signatures may form additional pathogenic subsets that are relevant to neurodegeneration. However, the significance of such MHC-II and IFN-I signatures remains elusive. We demonstrate here that these microglial subsets play intrinsic roles in orchestrating neurotoxic properties of neurotoxic Eomes⁺ Th cells under the neurodegeneration-associated phase of experimental autoimmune encephalomyelitis (EAE) that corresponds to progressive multiple sclerosis (MS). Microglia acquire IFN-signature after sensing ectopically expressed long interspersed nuclear element-1 (L1) gene. Furthermore, ORF1, an L1-encoded protein aberrantly expressed in the diseased central nervous system (CNS), stimulated Eomes⁺ Th cells after Trem2-dependent ingestion and presentation in MHC-II context by microglia. Interestingly, administration of an L1 inhibitor significantly ameliorated neurodegenerative symptoms of EAE concomitant with reduced accumulation of Eomes⁺ Th cells in the CNS. Collectively, our data highlight a critical contribution of new microglia subsets as a neuroinflammatory hub in immune-mediated neurodegeneration.

Keywords: microglia; neurodegeneration; progressive multiple sclerosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Central Nervous System / metabolism
Encephalomyelitis, Autoimmune, Experimental* / pathology
Microglia* / metabolism
T-Lymphocytes, Helper-Inducer / metabolism

Grants and funding

This work was supported by Health and Labor Sciences Research Grants, Research on rare and intractable diseases, JSPS KAKENHI Grant Numbers 18H04045 and 20K07895 and 20K16294 and the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED (17ek0109097, 17ek0109155). Intramural Research Grant (30-5) for Neurological and Psychiatric Disorders of NCNP.