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Article

Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK

1
Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, Baltimore, MD 21201, USA
2
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine Street, Baltimore, MD 21201, USA
3
Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, 110 S. Paca Street, Baltimore, MD 21201, USA
4
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD 21201, USA
*
Author to whom correspondence should be addressed.
Academic Editors: João Paulo Longo and Luís Alexandre Muehlmann
Pharmaceutics 2021, 13(11), 1841; https://doi.org/10.3390/pharmaceutics13111841
Received: 3 September 2021 / Revised: 23 October 2021 / Accepted: 28 October 2021 / Published: 2 November 2021
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. View Full-Text
Keywords: inflammation; innate immunity; macrophages; Toll-like receptors; TLR; NF-κB; p38 MAPK; sepsis; poly(lactic acid); PLA; lactate; nanoparticles; microparticles inflammation; innate immunity; macrophages; Toll-like receptors; TLR; NF-κB; p38 MAPK; sepsis; poly(lactic acid); PLA; lactate; nanoparticles; microparticles
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MDPI and ACS Style

Lasola, J.J.M.; Cottingham, A.L.; Scotland, B.L.; Truong, N.; Hong, C.C.; Shapiro, P.; Pearson, R.M. Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK. Pharmaceutics 2021, 13, 1841. https://doi.org/10.3390/pharmaceutics13111841

AMA Style

Lasola JJM, Cottingham AL, Scotland BL, Truong N, Hong CC, Shapiro P, Pearson RM. Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK. Pharmaceutics. 2021; 13(11):1841. https://doi.org/10.3390/pharmaceutics13111841

Chicago/Turabian Style

Lasola, Jackline J.M., Andrea L. Cottingham, Brianna L. Scotland, Nhu Truong, Charles C. Hong, Paul Shapiro, and Ryan M. Pearson. 2021. "Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK" Pharmaceutics 13, no. 11: 1841. https://doi.org/10.3390/pharmaceutics13111841

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