Transcription cofactor GRIP1 differentially affects myeloid cell-driven neuroinflammation and response to IFN-β therapy

Macrophages (M Phi) and microglia (MG) are critical in the pathogenesis of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Glucocorticoids (GCs) and interferon beta (IFN-beta) 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-beta. M Phi/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.

Automated summary

Macrophages and microglia play critical roles in neuroinflammation, and the deletion of GRIP1 can reduce the severity of EAE. Interestingly, the loss of GRIP1 also blunted the therapeutic properties of IFN-beta while promoting the persistence of a homeostatic microglia signature. The results uncover the multifaceted function of type I IFN in the pathogenesis and therapy of MS/EAE, and reveal an unexpectedly permissive role of myeloid cell GRIP1 in neuroinflammation.