Targeting Microglial Immunometabolism in Neuroinflammation: Molecular Mechanisms and Emerging Nanotherapeutic Strategies

Abstract

Brain resident immune cells (microglia) have critical functions in neuro-homeostasis and inflammation. In many neurodegenerative diseases, neuroinflammation is a common pathological process that occurs as a result of the persistent activation of microglia by stimuli. Microglia were once thought to be either "pro" or "anti" inflammatory, but more recently, it has been recognized that immunometabolism is also important in the phenotypical determination of microglia, and metabolic reprogramming is a key factor in resting microglial homeostasis and the transition into a neuro-inflammatory cell state. One of the key parameters that affect the metabolic profile of microglia is oxidative signaling. Reactive oxygen species (ROS) that were previously believed to be side products of metabolism that are toxic is now recognized as important signaling molecules that can impact gene expression and activate innate immune responses. A mitochondrial dysfunction, characterized by dysfunctional metabolism, ROS generation and dynamics, in turn, exacerbates neuro-inflammation and causes microglial homeostasis destabilization. Redox regulation and mitochondrial function are important in the disease process of neuro-inflammation. Therapeutic strategies based on nanotechnology with properties directly interacting with these synergic mechanisms can be used for the treatment of neurodegenerative diseases. Nanotechnology nanocarrier systems can be used to deliver targeted therapeutics and antioxidant nanomaterials as well as mitochondria targeted drugs across the blood brain barrier. However, the diversity of microglia and the safety of nanomaterials are issues that have to be taken care of. In translational research, unifying models and combining more targeted strategies for clinical application are the new promising in this field.