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.
Highlights
Severe inflammation is a complex and global multi-step physiological process implicated in the development of a systemic dysregulated immune environment
Of note, when we look at IκB degradation as a marker of NF-κB activation, we see that poly(lactic acid) (PLA) particles show similar protein levels to PS and poly(methyl methacrylate) (PMMA), all of which were lower than for LPS alone and LPS plus soluble lactic acid (sLA)
This work establishes that immunomodulatory nanoparticles (iNPs) take advantage of multiple mechanisms to mitigate severe inflammatory responses and suggests a novel multimodal approach to improve prospects for patients with sepsis and other inflammation-mediated diseases
Summary
Severe inflammation is a complex and global multi-step physiological process implicated in the development of a systemic dysregulated immune environment. Previous attempts to address and manage severe inflammation and sepsis have focused on the development of single molecular agents targeted against specific molecules or aspects of molecular pathways implicated in the development of the Pharmaceutics 2021, 13, 1841. It has been hypothesized that these attempts have failed because of the profound clinical heterogeneity of sepsis, the lack of fundamental understandings of the different endotypes of sepsis, and treatments that have been targeted towards only a single molecular pathway, leaving redundant pathways associated with immune activation and a multifaceted immune dysfunction unaddressed [5,6]. A significant need exists to develop multimodal therapeutics to address the complexity of immune responses present in severe inflammation and sepsis
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