Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF- B and p38 MAPK
AuthorLasola, Jackline Joy
Hong, Charles C., 1967-
Shapiro, Paul, Ph.D.
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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-altmaleic 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 (BMMFs). Additionally, we showed that iNPs mitigate proinflammatory cytokine secretions induced by LPS via a time- and composition-dependent abrogation of NF- B 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.
DescriptionThe article processing charges (APC) for this open access article were partially funded by the Health Sciences and Human Services Library's Open Access Publishing Fund for Early-Career Researchers.
Rights/TermsAttribution-NonCommercial-NoDerivatives 4.0 International
Myeloid Differentiation Factor 88
p38 Mitogen-Activated Protein Kinases
Receptors, Phospholipase A2
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/21116
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Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International