Anti-Inflammatory Strategy for M2 Microglial Polarization Using Retinoic Acid-Loaded Nanoparticles

Abstract

Inflammatory mechanisms triggered by microglial cells are involved in the pathophysiology of several brain disorders, hindering repair. Herein, we propose the use of retinoic acid-loaded polymeric nanoparticles (RA-NP) as a means to modulate microglia response towards an anti-inflammatory and neuroprotective phenotype (M2). RA-NP were first confirmed to be internalized by N9 microglial cells; nanoparticles did not affect cell survival at concentrations below 100 μg/mL. Then, immunocytochemical studies were performed to assess the expression of pro- and anti-inflammatory mediators. Our results show that RA-NP inhibited LPS-induced release of nitric oxide and the expression of inducible nitric oxide synthase and promoted arginase-1 and interleukin-4 production. Additionally, RA-NP induced a ramified microglia morphology (indicative of M2 state), promoting tissue viability, particularly neuronal survival, and restored the expression of postsynaptic protein-95 in organotypic hippocampal slice cultures exposed to an inflammatory challenge. RA-NP also proved to be more efficient than the free equivalent RA concentration. Altogether, our data indicate that RA-NP may be envisioned as a promising therapeutic agent for brain inflammatory diseases.

Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases

“…All these data suggest that retinoids are candidates for the treatment of neuroinflammation. Indeed, the use of RA-loaded polymeric nanoparticles (RA-NPs) modulates the murine microglial response towards an anti-inflammatory and neuroprotective phenotype (M2-like) in organotypic hippocampal slice cultures [ 143 ]. Recently, the intravenous administration of RA-NPs was shown to prevent ischemic injury in the immature brains of 2-day-old mice, demonstrating the role of RA in the control of neuroinflammation [ 144 ].…”

Reactive Oxygen Species‐Responsive Nanoparticles for the Treatment of Ischemic Stroke

“…[9] There is an abundance of experimental and clinical research supporting ROS as a promising therapeutic target for acute ischemic stroke. [16][17][18] For example, Liu and colleagues have demonstrated that melanin NPs (MeNPs) scavenge multiple reactive oxygen and nitrogen species (RONS), suppress RONS-induced inflammation, and are neuroprotective in vitro. On the other hand, several promising antioxidant nanoparticles (NPs) have been developed in recent years, with the perspective capacity of suppressing ROS-induced damage following ischemic stroke.…”

Regenerative Medicine Therapies for Targeting Neuroinflammation After Stroke

“…Cerebral ischemia also activates important delayed endogenous repair processes such as BBB repair, neurogenesis, and angiogenesis that are important for functional recovery and patient rehabilitation in clinical settings, and evidence suggests that the sub-acute phase of inflammation plays a key role in this process. The anti-inflammatory phenotype of microglia exhibits neuroprotective and anti-inflammatory effects during the delayed phase of post-stroke inflammation, producing anti- inflammatory cytokines such as IL-10, transforming growth factor (TGF)-β, IL-4, and IL-13, as well as scavenge receptors, contributing to inhibiting inflammation and promoting tissue repair mechanisms ( 28 ). Of those, neurogenesis—known to take place in the sub granular zone of the dentate gyrus of the hippocampus and in the sub ventricular zone adjacent to the third ventricle ( 29 )—is increased following experimental stroke ( 30 ), and is regulated by inflammatory mediators expressed during the acute phase of stroke ( 31 ).…”

“…Biocompatibility was assessed in vitro and in vivo , with NPs demonstrating no obvious toxicity. Another type of NPs, retinoic acid-loaded polymeric NPs (RA-NP) have been developed to modulate microglial response toward an anti-inflammatory and somehow neuroprotective phenotype ( 28 ). RA-NP were internalized by murine N9 microglial cell line and inhibited LPS-induced iNOS expression and NO release, whilst promoting arginase-1 and IL-4 production.…”