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A Soluble PrPC Derivative and Membrane-Anchored PrPC in Extracellular Vesicles Attenuate Innate Immunity by Engaging the NMDA-R/LRP1 Receptor Complex

Elisabetta Mantuano, Pardis Azmoon, Michael A. Banki, Christina J. Sigurdson, Wendy M. Campana and Steven L. Gonias
J Immunol January 1, 2022, 208 (1) 85-96; DOI: https://doi.org/10.4049/jimmunol.2100412
Elisabetta Mantuano
*Department of Pathology, University of California San Diego, La Jolla, CA;
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Pardis Azmoon
*Department of Pathology, University of California San Diego, La Jolla, CA;
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Michael A. Banki
*Department of Pathology, University of California San Diego, La Jolla, CA;
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Christina J. Sigurdson
*Department of Pathology, University of California San Diego, La Jolla, CA;
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Wendy M. Campana
†Department of Anesthesiology and Program in Neurosciences, University of California San Diego, La Jolla, CA; and
‡Veterans Administration San Diego Healthcare System, San Diego, CA
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Steven L. Gonias
*Department of Pathology, University of California San Diego, La Jolla, CA;
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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.

Abstract

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-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 PrPC is the essential EV component required for the observed immune regulatory activity of human plasma EVs. S-PrP and EV-associated PrPC 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 PrPC may have broad anti-inflammatory activity.

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Footnotes

  • This work was supported by National Heart, Lung, and Blood Institute Grant R01 HL136395 (to S.L.G.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    BMDM
    bone marrow–derived macrophage
    DXM
    dextromethorphan hydrobromide
    EI-tPA
    enzymatically inactive tissue-type plasminogen activator
    EV
    extracellular vesicle
    IMQ
    imiquimod
    L18-MDP
    L18-muramyl dipeptide
    LRP1
    low-density lipoprotein receptor–related protein-1
    LTA
    lipoteichoic acid
    α2M
    α2-macroglobulin
    NTA
    nanoparticle tracking analysis
    PI-PLC
    phosphatidylinositol-specific phospholipase C
    pMac
    peritoneal macrophage
    PrPC
    cellular prion protein
    PRR
    pattern recognition receptor
    qPCR
    quantitative PCR
    RAP
    receptor-associated protein
    SFK
    Src family kinase
    SFM
    serum-free medium
    S-PrP
    soluble derivative of PrPC
    TEM
    transmission electron microscopy
    tPA
    tissue-type plasminogen activator
    UC
    ultracentrifugation
    WT
    wild-type

  • Received April 30, 2021.
  • Accepted October 19, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (1)
The Journal of Immunology
Vol. 208, Issue 1
1 Jan 2022
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A Soluble PrPC Derivative and Membrane-Anchored PrPC in Extracellular Vesicles Attenuate Innate Immunity by Engaging the NMDA-R/LRP1 Receptor Complex
Elisabetta Mantuano, Pardis Azmoon, Michael A. Banki, Christina J. Sigurdson, Wendy M. Campana, Steven L. Gonias
The Journal of Immunology January 1, 2022, 208 (1) 85-96; DOI: 10.4049/jimmunol.2100412

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A Soluble PrPC Derivative and Membrane-Anchored PrPC in Extracellular Vesicles Attenuate Innate Immunity by Engaging the NMDA-R/LRP1 Receptor Complex
Elisabetta Mantuano, Pardis Azmoon, Michael A. Banki, Christina J. Sigurdson, Wendy M. Campana, Steven L. Gonias
The Journal of Immunology January 1, 2022, 208 (1) 85-96; DOI: 10.4049/jimmunol.2100412
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