Immunomodulatory nanoparticles mitigate macrophage inflammation via inhibition of pamp interactions and lactate-mediated functional reprogramming of nf-κb and p38 mapk
Author
Lasola, Jackline Joy MartínCottingham, Andrea L.
Scotland, Brianna L.
Truong, Nhu
Hong, Charles C.
Shapiro, Paul
Pearson, Ryan M.
Date
2021-11-02Journal
PharmaceuticsPublisher
MDPI AGType
Article
Metadata
Show full item recordAbstract
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 HealthKeyword
InflammationInnate immunity
Lactate
Macrophages
Microparticles
Nanoparticles
NF-κB
P38 MAPK
PLA
Poly(lactic acid)
Sepsis
TLR
Toll-like receptors
Identifier to cite or link to this item
http://hdl.handle.net/10713/17152ae974a485f413a2113503eed53cd6c53
10.3390/pharmaceutics13111841