Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury

Abstract

Microglial cells, which are highly plastic, immediately respond to any change in the microenvironment by becoming activated and shifting the phenotype toward neurotoxicity or neuroprotection. The polarization of microglia/macrophages after spinal cord injury (SCI) seems to be a dynamic process and can change depending on the microenvironment, stage, course, and severity of the posttraumatic process. Effective methods to modulate microglia toward a neuroprotective phenotype in order to stimulate neuroregeneration are actively sought for. In this context, available approaches that can selectively impact the polarization of microglia/macrophages regulate synthesis of trophic factors and cytokines/chemokines in them, and their phagocytic function and effects on the course and outcome of SCI are discussed in this review.

Keywords: microglia; modulation; neuroregeneration; phenotypes; spinal cord injury.

FIGURE 1

Microglial signaling pathways determining development of cells with divergent abilities. Classical activation of the NF-κB signaling is initiated by TLRs, as well as other cell surface receptors, including specific IL-1 and TNF, and provides M1 polarization of microglia. PI3K/Akt/mTOR is triggered through the CD74 receptor, whose activation is promoted by MIF. There is quite contradictory evidence that this pathway affects the shift of the microglia/macrophage phenotype toward M1 or M2. Anti-inflammatory cytokines IL-10 and IL-4 induce STAT3 and STAT6 phosphorylation, respectively, via JAK1, which promotes polarization toward the M2 phenotype. The activation of STAT1, in turn, leads to polarization toward a neurotoxic M2 phenotype of microglia. Normally, there is a balance between the activation of STAT1 and STAT3/STAT6 that strictly regulates the microglia polarization and activity.