| First Author | Mantuano E | Year | 2022 |
| Journal | J Immunol | Volume | 208 |
| Issue | 1 | Pages | 85-96 |
| PubMed ID | 34810220 | Mgi Jnum | J:333026 |
| Mgi Id | MGI:7432435 | Doi | 10.4049/jimmunol.2100412 |
| Citation | Mantuano E, et al. (2022) A Soluble PrP(C) Derivative and Membrane-Anchored PrP(C) in Extracellular Vesicles Attenuate Innate Immunity by Engaging the NMDA-R/LRP1 Receptor Complex. J Immunol 208(1):85-96 |
| abstractText | Nonpathogenic cellular prion protein (PrP(C)) demonstrates anti-inflammatory activity; however, the responsible mechanisms are incompletely defined. PrP(C) exists as a GPI-anchored membrane protein in diverse cells; however, PrP(C) may be released from cells by ADAM proteases or when packaged into extracellular vesicles (EVs). In this study, we show that a soluble derivative of PrP(C) (S-PrP) counteracts inflammatory responses triggered by pattern recognition receptors in macrophages, including TLR2, TLR4, TLR7, TLR9, NOD1, and NOD2. S-PrP also significantly attenuates the toxicity of LPS in mice. The response of macrophages to S-PrP is mediated by a receptor assembly that includes the N-methyl-d-aspartate receptor (NMDA-R) and low-density lipoprotein receptor-related protein-1 (LRP1). PrP(C) was identified in EVs isolated from human plasma. These EVs replicated the activity of S-PrP, inhibiting cytokine expression and IkappaBalpha phosphorylation in LPS-treated macrophages. The effects of plasma EVs on LPS-treated macrophages were blocked by PrP(C)-specific Ab, by antagonists of LRP1 and the NMDA-R, by deleting Lrp1 in macrophages, and by inhibiting Src family kinases. Phosphatidylinositol-specific phospholipase C dissociated the LPS-regulatory activity from EVs, rendering the EVs inactive as LPS inhibitors. The LPS-regulatory activity that was lost from phosphatidylinositol-specific phospholipase C-treated EVs was recovered in solution. Collectively, these results demonstrate that GPI-anchored PrP(C) is the essential EV component required for the observed immune regulatory activity of human plasma EVs. S-PrP and EV-associated PrP(C) regulate innate immunity by engaging the NMDA-R/LRP1 receptor system in macrophages. The scope of pattern recognition receptors antagonized by S-PrP suggests that released forms of PrP(C) may have broad anti-inflammatory activity. |
