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    Immunomodulatory nanoparticles mitigate macrophage inflammation via inhibition of pamp interactions and lactate-mediated functional reprogramming of nf-κb and p38 mapk

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    Author
    Lasola, Jackline Joy Martín
    Cottingham, Andrea L.
    Scotland, Brianna L.
    Truong, Nhu
    Hong, Charles C.
    Shapiro, Paul
    Pearson, Ryan M.
    Date
    2021-11-02
    Journal
    Pharmaceutics
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/pharmaceutics13111841
    Abstract
    Inflammation is a key homeostatic process involved in the body’s response to a multitude of disease states including infection, autoimmune disorders, cancer, and other chronic conditions. When the initiating event is poorly controlled, severe inflammation and globally dysregulated immune responses can occur. To address the lack of therapies that efficaciously address the multiple aspects of the dysregulated immune response, we developed cargo-less immunomodulatory nanoparticles (iNPs) comprised of poly(lactic acid) (PLA) with either poly(vinyl alcohol) (PVA) or poly(ethylene-alt-maleic acid) (PEMA) as stabilizing surfactants and investigated the mechanisms by which they exert their inherent anti-inflammatory effects. We identified that iNPs leverage a multimodal mechanism of action by physically interfering with the interactions between pathogen-associated molecular patterns (PAMPs) and bone marrow-derived macrophages (BMMΦs). Additionally, we showed that iNPs mitigate proinflammatory cytokine secretions induced by LPS via a time-and composition-dependent abrogation of NF-κB p65 and p38 MAPK activation. Lastly, inhibition studies were performed to establish the role of a pH-sensing G-protein-coupled receptor, GPR68, on contributing to the activity of iNPs. These data provide evidence for the multimodal mechanism of action of iNPs and establish their potential use as a novel therapeutic for the treatment of severe inflammation. © 2021 by the authors.
    Sponsors
    National Institutes of Health
    Keyword
    Inflammation
    Innate immunity
    Lactate
    Macrophages
    Microparticles
    Nanoparticles
    NF-κB
    P38 MAPK
    PLA
    Poly(lactic acid)
    Sepsis
    TLR
    Toll-like receptors
    Show allShow less
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17152
    ae974a485f413a2113503eed53cd6c53
    10.3390/pharmaceutics13111841
    Scopus Count
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