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Anti-Inflammatory Strategy for M2 Microglial Polarization Using Retinoic Acid-Loaded Nanoparticles
Marta Machado-Pereira1, Tiago Santos1, Lino Ferreira2,3
1Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Rua Marquês d'Ávila e Bolama, 6201-001 Covilhã, Portugal.
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.
Insights
Retinoic acid-loaded nanoparticles (RA-NP) reprogram inflammatory microglia to an M2 phenotype. This approach reduces brain inflammation and enhances neuronal survival, offering a promising therapy for neurological disorders.
Area of Science:
- Neuroscience
- Biomaterials Science
- Immunology
Background:
- Microglial cell activation drives brain inflammation and hinders neural repair in various disorders.
- Modulating microglial phenotype is crucial for developing effective neuroprotective strategies.
Purpose of the Study:
- To investigate retinoic acid-loaded polymeric nanoparticles (RA-NP) for modulating microglial response.
- To evaluate RA-NP's potential in promoting an anti-inflammatory and neuroprotective M2 phenotype in microglia.
Main Methods:
- Characterization of RA-NP internalization and cytotoxicity in N9 microglial cells.
- Immunocytochemical analysis of pro- and anti-inflammatory mediator expression (nitric oxide, inducible nitric oxide synthase, arginase-1, interleukin-4).
- Assessment of microglia morphology, neuronal survival, and postsynaptic protein-95 expression in organotypic hippocampal slice cultures.
Main Results:
- RA-NP were effectively internalized by microglial cells without significant cytotoxicity.
- RA-NP treatment inhibited lipopolysaccharide (LPS)-induced nitric oxide and inducible nitric oxide synthase, while promoting arginase-1 and interleukin-4.
- RA-NP induced an M2 microglia morphology, enhanced neuronal survival, and restored postsynaptic protein-95 expression in inflamed brain slices, outperforming free retinoic acid.
Conclusions:
- RA-NP effectively shift microglia towards an anti-inflammatory M2 phenotype.
- RA-NP demonstrate significant neuroprotective effects, promoting tissue viability and neuronal survival.
- RA-NP represent a promising therapeutic candidate for managing brain inflammatory diseases.
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