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

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 c...

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Autores principales:	Jackline Joy Martín Lasola, Andrea L. Cottingham, Brianna L. Scotland, Nhu Truong, Charles C. Hong, Paul Shapiro, Ryan M. Pearson
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	inflammation innate immunity macrophages Toll-like receptors TLR NF-κB Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/1592704ca67e4380840c5bbd9144f8b6
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spelling	oai:doaj.org-article:1592704ca67e4380840c5bbd9144f8b62021-11-25T18:41:05ZImmunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK10.3390/pharmaceutics131118411999-4923https://doaj.org/article/1592704ca67e4380840c5bbd9144f8b62021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1841https://doaj.org/toc/1999-4923Inflammation 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.Jackline Joy Martín LasolaAndrea L. CottinghamBrianna L. ScotlandNhu TruongCharles C. HongPaul ShapiroRyan M. PearsonMDPI AGarticleinflammationinnate immunitymacrophagesToll-like receptorsTLRNF-κBPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1841, p 1841 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	inflammation innate immunity macrophages Toll-like receptors TLR NF-κB Pharmacy and materia medica RS1-441
spellingShingle	inflammation innate immunity macrophages Toll-like receptors TLR NF-κB Pharmacy and materia medica RS1-441 Jackline Joy Martín Lasola Andrea L. Cottingham Brianna L. Scotland Nhu Truong Charles C. Hong Paul Shapiro Ryan M. Pearson Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK
description	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.
format	article
author	Jackline Joy Martín Lasola Andrea L. Cottingham Brianna L. Scotland Nhu Truong Charles C. Hong Paul Shapiro Ryan M. Pearson
author_facet	Jackline Joy Martín Lasola Andrea L. Cottingham Brianna L. Scotland Nhu Truong Charles C. Hong Paul Shapiro Ryan M. Pearson
author_sort	Jackline Joy Martín Lasola
title	Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK
title_short	Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK
title_full	Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK
title_fullStr	Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK
title_full_unstemmed	Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK
title_sort	immunomodulatory nanoparticles mitigate macrophage inflammation via inhibition of pamp interactions and lactate-mediated functional reprogramming of nf-κb and p38 mapk
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1592704ca67e4380840c5bbd9144f8b6
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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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