Transcription cofactor GRIP1 differentially affects myeloid cell-driven neuroinflammation and response to IFN-β therapy. Academic Article uri icon

Overview

abstract

  • Macrophages (MФ) and microglia (MG) are critical in the pathogenesis of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Glucocorticoids (GCs) and interferon β (IFN-β) are frontline treatments for MS, and disrupting each pathway in mice aggravates EAE. Glucocorticoid receptor-interacting protein 1 (GRIP1) facilitates both GR and type I IFN transcriptional actions; hence, we evaluated the role of GRIP1 in neuroinflammation. Surprisingly, myeloid cell-specific loss of GRIP1 dramatically reduced EAE severity, immune cell infiltration of the CNS, and MG activation and demyelination specifically during the neuroinflammatory phase of the disease, yet also blunted therapeutic properties of IFN-β. MФ/MG transcriptome analyses at the bulk and single-cell levels revealed that GRIP1 deletion attenuated nuclear receptor, inflammatory and, interestingly, type I IFN pathways and promoted the persistence of a homeostatic MG signature. Together, these results uncover the multifaceted function of type I IFN in MS/EAE pathogenesis and therapy, and an unexpectedly permissive role of myeloid cell GRIP1 in neuroinflammation.

publication date

  • January 4, 2021

Research

keywords

  • Encephalomyelitis, Autoimmune, Experimental
  • Interferon-beta
  • Macrophages
  • Multiple Sclerosis
  • Nuclear Receptor Coactivator 2

Identity

PubMed Central ID

  • PMC7555412

Scopus Document Identifier

  • 85092885735

Digital Object Identifier (DOI)

  • 10.1111/ene.12698

PubMed ID

  • 33045064

Additional Document Info

volume

  • 218

issue

  • 1