A soluble PrPC derivative and membrane-anchored PrPC in extracellular vesicles attenuate innate immunity by engaging the NMDA-R/LRP1 receptor complex

作者：E. Mantuano, Pardis Azmoon, Michael A. Banki, C. Sigurdson, W. Campana, S. Gonias · 发表于：Journal of Immunology · 年份：2021 · DOI：10.4049/jimmunol.2100412 · 被引用次数：18 · 研究领域：Medicine

Key Points Shed PrPC derivatives and PrPC in extracellular vesicles regulate innate immunity. The macrophage NMDA-R/LRP1 complex mediates the activity of PrPC released by cells. The NMDA-R/LRP1 complex functions as an extracellular vesicle receptor in target cells. Nonpathogenic cellular prion protein (PrPC) demonstrates anti-inflammatory activity; however, the responsible mechanisms are incompletely defined. PrPC exists as a GPI-anchored membrane protein in diverse cells; however, PrPC 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 PrPC (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). PrPC was identified in EVs isolated from human plasma. These EVs replicated the activity of S-PrP, inhibiting cytokine expression and IκBα phosphorylation in LPS-treated macrophages. The effects of plasma EVs on LPS-treated macrophages were blocked by PrPC-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...