CnpPromoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis

Abstract

The ERK1/2 signaling pathway promotes myelin wrapping during development and remyelination, and sustained ERK1/2 activation in the oligodendrocyte (OL) lineage results in hypermyelination of the CNS. We therefore hypothesized that increased ERK1/2 signaling in the OL lineage would 1) protect against immune-mediated demyelination due to increased baseline myelin thickness and/or 2) promote enhanced remyelination and thus functional recovery after experimental autoimmune encephalomyelitis (EAE) induction. Cnp-Cre;Mek1DD-eGFP/+ mice that express a constitutively active form of MEK1 (the upstream activator of ERK1/2) in the OL lineage, exhibited a significant decrease in EAE clinical severity compared to controls. However, experiments using tamoxifen-inducible Plp-CreERT;Mek1DD-eGFP/+ or Pdgfrα-CreERT;Mek1DD-eGFP mice revealed this was not solely due to a protective or reparative effect resulting from MEK1DD expression specifically in the OL lineage. Because EAE is an immune-mediated disease, we examined Cnp-Cre; Mek1DD-eGFP/+ splenic immune cells for recombination. Surprisingly, GFP+ recombined CD19+ B-cells, CD11b+ monocytes, and CD3+ T-cells were noted when Cre expression was driven by the Cnp promoter. While ERK1/2 signaling in monocytes and T-cells is associated with proinflammatory activation, fewer studies have examined ERK1/2 signaling in B-cell populations. After in vitro stimulation, MEK1DD-expressing B-cells exhibited a 3-fold increase in CD138+ plasmablasts and a 5-fold increase in CD5+CD1dhi B-cells compared to controls. Stimulated MEK1DD-expressing B-cells also exhibited an upregulation of IL-10, known to suppress the initiation of EAE when produced by CD5+CD1dhi regulatory B-cells. Taken together, our data support the conclusion that sustained ERK1/2 activation in B-cells suppresses immune-mediated demyelination via increasing activation of regulatory B10 cells.

Antagonistic actions of PAK1 and NF2/Merlin drive myelin membrane expansion in oligodendrocytes

“…Interestingly, OL cultures lacking PAK1 expression (Figure 7a) had larger myelin membrane surface area than control OLs (Figure 7b,c), while maintaining the same percentage of differentiated OLs relative to the total oligodendroglial population (Figure S5). These results not only confirm that myelin membrane expansion in vitro recapitulates myelin thickening in vivo, but also that myelin thickening in Pak1cKO mice is unlikely to be due to Cnp-Cre recombination in other cell types (Jeffries et al, 2020;Tognatta et al, 2017).…”

Immunosuppressive Mechanisms of Regulatory B Cells

“…STAT3 phosphorylation is increased in CD40-activated transitional B cells of healthy subjects but not in those from SLE patients ( 26 ). In addition, CREB, p38 MAPK, ERK1/2, and PI3Kδ have been described to be required for IL-10 upregulation following TLR and/or CD40L stimulation ( 58 , 67 , 110 ). c-Maf, a well-known transactivator of IL-10 in various cell types, has also been shown to mediate IL-10 transcription by LPS-stimulated murine B cells ( 111 ).…”

mTOR Signaling Regulates Metabolic Function in Oligodendrocyte Precursor Cells and Promotes Efficient Brain Remyelination in the Cuprizone Model

“…In this study, we used tamoxifen-inducible Ng2-Cre ERT ; Mtor fl/fl mice to delete Mtor from adult OPCs that generate new OLs responsible for remyelination. While existing mature OLs appear to contribute to remyelination in the rodent CNS under specific circumstances, such as a motor learning paradigm or genetic modulation (Mason et al, 2000;Bacmeister et al, 2020;Jeffries et al, 2020), published studies indicate that remyelination is otherwise largely a result of new OL production (Targett et al, 1996;Crawford et al, 2016). We show that Mtor deletion from adult OPCs significantly delays remyelination after CPZ demyelination but has no effect on remyelination after LPC demyelination of either the spinal cord or brain, suggesting that Mtor deletion and CPZ treatment may target a similar pathway to impair remyelination.…”