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dc.contributor.authorLasola, Jackline Joy Martín
dc.contributor.authorCottingham, Andrea L.
dc.contributor.authorScotland, Brianna L.
dc.contributor.authorTruong, Nhu
dc.contributor.authorHong, Charles C.
dc.contributor.authorShapiro, Paul
dc.contributor.authorPearson, Ryan M.
dc.date.accessioned2021-11-18T18:39:10Z
dc.date.available2021-11-18T18:39:10Z
dc.date.issued2021-11-02
dc.identifier.urihttp://hdl.handle.net/10713/17152
dc.description.abstractInflammation 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.en_US
dc.description.sponsorshipNational Institutes of Healthen_US
dc.description.urihttps://doi.org/10.3390/pharmaceutics13111841en_US
dc.language.isoenen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofPharmaceuticsen_US
dc.subjectInflammationen_US
dc.subjectInnate immunityen_US
dc.subjectLactateen_US
dc.subjectMacrophagesen_US
dc.subjectMicroparticlesen_US
dc.subjectNanoparticlesen_US
dc.subjectNF-κBen_US
dc.subjectP38 MAPKen_US
dc.subjectPLAen_US
dc.subjectPoly(lactic acid)en_US
dc.subjectSepsisen_US
dc.subjectTLRen_US
dc.subjectToll-like receptorsen_US
dc.titleImmunomodulatory nanoparticles mitigate macrophage inflammation via inhibition of pamp interactions and lactate-mediated functional reprogramming of nf-κb and p38 mapken_US
dc.typeArticleen_US
dc.identifier.doi10.3390/pharmaceutics13111841
dc.source.volume13
dc.source.issue11


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