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.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system (CNS) and whose etiology remains unknown (Bishop and Rumrill, 2015; Dendrou et al, 2015; Lassmann, 2011)
Only a small group of 20 genes overlapped in the two datasets; that is, they were repressed by both Dex and interferon β (IFN-β), but those encoding key proinflammatory cytokines Tnf, Il1a, Il1b, and Il12b were among them (Fig. S1 A, top right, underlined)
We have previously established that Glucocorticoid receptor–interacting protein 1 (GRIP1) mediates antiinflammatory actions of GC receptor (GR) in bone marrow (BM)-derived primary MV (BMMV) by potentiating both activation of anti-inflammatory genes (e.g., Tsc22d3, Dusp1) and repression of proinflammatory ones such as Tnf, Il1a, and Il1b (Rollins et al, 2017)
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system (CNS) and whose etiology remains unknown (Bishop and Rumrill, 2015; Dendrou et al, 2015; Lassmann, 2011). MV rely on bone marrow (BM)–derived precursors for renewal and are able to circulate into the blood as monocytes or reside in tissues, depending on their role and immunological state (Goldmann et al, 2016) Both cell types display high plasticity (Holtman et al, 2017; Italiani and Boraschi, 2014; Murray, 2017; Shemer et al, 2015) and can have similar roles, especially during inflammation. In disease, such as MS, together with CNSinfiltrating MV, MG shape the immune responses through antigen presentation, phagocytosis of myelin, and cytokine secretion (Almolda et al, 2011; Fourgeaud et al, 2016; Franco and Fernandez-Suarez, 2015). These functions place MG and MV as central effectors of neuroinflammation, but their specific and potentially divergent contribution to MS pathogenesis remains poorly defined
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