Restorative therapy using microglial depletion and repopulation for central nervous system injuries and diseases

Abstract

Microglia are important resident immune cells in the central nervous system (CNS) and play an important role in its development, homeostasis, and disease treatments. Activated microglia perform diverse functions in mouse models of CNS neurodegenerative diseases or deficits. In humans, microglia have been linked to various neurodegenerative diseases. Following brain or spinal cord injury, microglia express pro- and anti-inflammatory phenotypes at different stages of recovery. With the development of pharmacological and genetic tools for microglial depletion, studies have demonstrated that microglial depletion exerts both positive and negative effects in the treatment of CNS diseases. Notably, microglial depletion provides an empty niche that stimulates production of new microglia. Microglial depletion and repopulation can not only treat diseases by eliminating dysfunctional microglia but can also provide an indication of the molecular mechanisms of diseases. Although this approach has shown impressive results, its use is still in its infancy. In this review, we summarize the current pharmacological and genetic tools for microglial depletion and highlight recent advances in microglial repopulation therapy for the treatment and functional recovery of neurological diseases and deficits. Finally, we briefly discuss the therapeutic challenges and prospective uses of microglial repopulation therapy.

Keywords: central nervous system; depletion; diseases; microglia; repopulation.

Figure 1

Approaches for microglial depletion and multiple sources of microglial repopulation. Robust methods for depleting microglia in vivo include clodronate liposomes, genetic models and CSF1R inhibitors. These methods deplete microglia in the CNS effectively. After withdraw the intervention, microglia repopulate and return to normal levels in 1–2 weeks. The repopulated microglia in the retina are not derived from nestin-positive progenitor cells. The repopulated microglia in the center arise from the residual microglia in the optic nerve, while the periphery-emerging microglia are from macrophages in the ciliary body/iris. Spinal microglia can reproduce rapidly after removal, which is mainly driven by the process of self-renewal. Microglia in the brain may repopulate in one of three ways: stimulation of microglia progenitor cells that express nestin, proliferation of residual microglia, or infiltration of peripheral mononuclear cells.

Figure 2

Different functions of activated and repopulated microglia in CNS diseases. Microglial activation leads to cognitive deficits through excessive synaptic pruning and inhibition of synaptic transmission. At the same time, these cells promote the release of inflammatory factors, stimulate plaque formation, and directly damage neurons, which leads to CNS diseases. Repopulated microglia not only suppress the inflammatory response, but also limit neuritic dystrophy by promoting the transition from diffuse to compact-like plaques. These cells can restore cognitive function by promoting synaptic transmission and inhibiting excessive synaptic pruning. Furthermore, repopulated microglia mediate neuroprotective effects by inducing IL-6 within neurons.