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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK
Author
Jackline Joy Martín Lasola 1   VIAFID ORCID Logo  ; Cottingham, Andrea L 2   VIAFID ORCID Logo  ; Scotland, Brianna L 2   VIAFID ORCID Logo  ; Truong, Nhu 2 ; Hong, Charles C 3 ; Shapiro, Paul 4 ; Pearson, Ryan M 4   VIAFID ORCID Logo 

 Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, Baltimore, MD 21201, USA; [email protected] 
 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine Street, Baltimore, MD 21201, USA; [email protected] (A.L.C.); [email protected] (B.L.S.); [email protected] (N.T.); [email protected] (P.S.) 
 Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, 110 S. Paca Street, Baltimore, MD 21201, USA; [email protected] 
 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine Street, Baltimore, MD 21201, USA; [email protected] (A.L.C.); [email protected] (B.L.S.); [email protected] (N.T.); [email protected] (P.S.); Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD 21201, USA 
First page
1841
Publication year
2021
Publication date
2021
Publisher
MDPI AG
e-ISSN
19994923
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2602162477
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.