Nutritional and Nanotechnological Modulators of Microglia

Abstract

Microglia are the essential responders to alimentary, pharmacological, and nanotechnological immunomodulators. These neural cells play multiple roles as surveyors, sculptors, and guardians of essential parts of complex neural circuitries. Microglia can play dual roles in the central nervous system; they can be deleterious and/or protective. The immunomodulatory effects of alimentary components, gut microbiota, and nanotechnological products have been investigated in microglia at the single-cell level and in vivo using intravital imaging approaches, and different biochemical assays. This review highlights some of the emerging questions and topics from studies involving alimentation, microbiota, nanotechnological products, and associated problems in this area of research. Some of the advantages and limitations of in vitro and in vivo models used to study the neuromodulatory effects of these factors, as well as the merits and pitfalls of intravital imaging modalities employed are presented.

Keywords: immunomodulation; intravital imaging; microbiota–gut–brain axis; microglia; nanodelivery systems; nanomedicine; neuroinflammation; nutrition.

Figure 1

(A) Molecular mechanism of dPGS binding to L-selectins and P-selectin ligands. (B) Fluorescence micrograph of fluorescently labeled dPGS (red) in microglia. Nuclei are labeled with Hoechst 33342 (blue).

Figure 2

Models of different complexity used to study the effects of immunomodulators in neural cells. In vivo models of neuroinflammation are most suitable for morphological and functional studies, while in vitro models of neural cells in 2D (primary and immortal dissociated cells) and 3D (neurospheres and brain slice cultures) are useful for morphological, mechanistic, and signaling studies. Isolated organelles can be used to investigate mechanisms of inflammation at the subcellular level. [*Hippocampus (hippos = horse; campos = sea monster); **neurons, microglia, astrocytes; ***organelles: mitochondria, lipid droplets, lysosomes, nucleoli.]

Figure 3

Organellar remodeling in inflammation. Multiple pro-inflammatory stimuli can disrupt redox homeostasis in microglia. Mitochondria are the major source of reactive oxygen species (ROS). Excessive ROS induces the formation of lipid bodies and impairs their communication with intracellular organelles. Several signal transduction pathways implicated in inflammation converge on the inflammasome. Inflammasome activation leads to the caspase activation and cytokine release. Modulation of these pathways can lead to resolution of inflammation or exacerbation with pyroptotic cell death.

Figure 4

LPS and IL-6 signaling in microglia. LPS can interact with membrane-bound TLR4 (canonical signaling) or can enter the cytosol independently from TLR4 (non-canonical signaling). The major cytosolic receptors for LPS are pro-inflammatory caspases. IL-6 binds either to the membrane receptor IL-6R (mIL-6R; classical signaling) or to the soluble IL-6 receptor (sIL-6R; trans-signaling). These receptor complexes subsequently bind to gp130 to initiate intracellular signaling cascades.

Figure 5

(A) Schematic representation of a quantum dot-based sensor for caspase activity. In the absence of caspase activity, there is fluorescence resonance energy transfer (FRET) between the quantum dot (QD) and the rhodamine molecule (Rd), and the fluorescence of the QD is quenched. In the presence of caspase activity, FRET is disrupted, and the QD is fluorescent. (B) Schematic representation of a ratiometric biosensor for caspase activity. In the absence of caspase activity, the dimerization-dependent green fluorescent protein (GFP) is dimerized with the partner protein B and is retained in the cytoplasm through a nuclear exclusion signal (NES). In the presence of caspase activity, the dimerization is disrupted, and B translocated to the nucleus using a nuclear localization signal (NLS), and associates with the dimerization-dependent red fluorescent protein (RFP). As a result, green fluorescence in the cytoplasm fades, and red fluorescence in the nucleus increases.