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

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.

Excel Template for Identifying Mouse Myeloid Cell-Types in the Central Nervous System Based on Single-Cell RNA Sequencing Data

“…We can understand the importance of cell clustering through the following example. When we analyzed another data (Table S2 of Mimouna et al) [33], both the reported and our results were not ideal. Analyzing the reasons, we nd that their data clustering methods are different from the other literatures mentioned above.…”

“…Of course, our cell identi cation process was not smooth sailing. When we analyzed another data (Table S2 of Mimouna et al) [33], we encounter thorny problems. In this report, Louvain graph-based community clustering was used to divide the cells into different clusters, and PanglaoDB was used to identify putative cell and/or activation state for each individual Louvain cluster.…”

“…The sources of gene expression data used in this paper are shown in Table 1 [10,[31][32][33]. The data in each literature are displayed in the form of Excel (Fig.…”

Steroid receptor coactivators – their role in immunity

“…In agreement with this observation, stimulation of SRC-3 with a small molecule stimulator MCB-613 ( 85 ) brings about enrichment of anti-inflammatory MΦs to promote the establishment and maintenance of a pro-reparative environment post myocardial infarction (MI) ( 86 ) ( Figure 2B ). Surprisingly, as opposed to its anti-inflammatory role in peripheral MΦs, SRC-2 drives neuroinflammation through activation of a proinflammatory program in microglia (MG) ( 87 ); conditional KO (cKO) of SRC-2 in myeloid cells significantly reduces experimental autoimmune encephalomyelitis (EAE) severity, which in part is associated with persistence of a homeostatic MG signature, rather than a pro-inflammatory profile and activity that are associated with SRC-2 deficiency in BM and WAT-resident MΦs ( Figure 2A ). This unexpected role of SRC-2 as a driving force of neuroinflammation indicates the functional versatility associated with this NCoA in different MΦ subtypes which is dependent on the environmental conditions and biological context.…”

Continuous injection of high-dose lipopolysaccharide modulates microglia polarization via TREM2 to alter the status of septic mice

“…Increasingly, it is demonstrated that in the presence of neuroin ammation, the production of IFN-β plays a neuroprotective role in many central neurological diseases, such as Multiple Sclerosis (MS) and Experimental Autoimmune Encephalomyelitis (EAE) [6][7][8]. IFN-β is used clinically as one of the drugs to alleviate the neuroin ammatory response in MS [9]. It can also reduce microglial responsiveness, microglial proliferation and neuroin ammation [10].…”