Advances in the research of the role of macrophage/microglia polarization-mediated inflammatory response in spinal cord injury

Abstract

It is often difficult to regain neurological function following spinal cord injury (SCI). Neuroinflammation is thought to be responsible for this failure. Regulating the inflammatory response post-SCI may contribute to the recovery of neurological function. Over the past few decades, studies have found that macrophages/microglia are one of the primary effector cells in the inflammatory response following SCI. Growing evidence has documented that macrophages/microglia are plastic cells that can polarize in response to microenvironmental signals into M1 and M2 macrophages/microglia. M1 produces pro-inflammatory cytokines to induce inflammation and worsen tissue damage, while M2 has anti-inflammatory activities in wound healing and tissue regeneration. Recent studies have indicated that the transition from the M1 to the M2 phenotype of macrophage/microglia supports the regression of inflammation and tissue repair. Here, we will review the role of the inflammatory response and macrophages/microglia in SCI and repair. In addition, we will discuss potential molecular mechanisms that induce macrophage/microglia polarization, with emphasis on neuroprotective therapies that modulate macrophage/microglia polarization, which will provide new insights into therapeutic strategies for SCI.

Keywords: inflammatory response; macrophages; mesenchymal stem cells; miRNA; microglia; polarization; spinal cord injury.

Figure 1

This figure shows the combination of pathophysiological events that occur post-SCI. This includes hemorrhage, oedema, inflammation, apoptosis, necrosis, oxidative damage, ischemia and vasospasm. Following primary injury, resident cells (astrocytes, microglia) are immediately activated and migrate to the site of injury. Subsequently, peripheral inflammatory cells, including neutrophils, macrophages and lymphocytes, infiltrate into the center of the damaged spinal cord. These activated immune cells can exacerbate the injury, causing neuronal death, which leads to axonal demyelination and disruption of synaptic transmission. In the subacute phase, fluid-filled cavities form in the center of the spinal cord. Astrocytes form a glial scar to isolate the damaged area. These sustained pathophysiological changes eventually lead to severe dysfunction below the damaged segment.

Figure 2

M1 and M2 macrophages/microglia have different roles in SCI. M1 macrophages/microglia are neurotoxic and release destructive factors that impair axon repair/regeneration. These cells can induce the necroptosis of astrocytes and promote the formation of the spinal cavity. In contrast, M2 macrophages/microglia have anti-inflammatory and neuroprotective effects, releasing neuroprotective factors such as IL-10 and TGF-β to improve SCI repair/regeneration. In addition, the M2 phenotype facilitates axon regeneration and angiogenesis by secreting activin A and matrix metalloproteinase 9 (MMP-9).

Figure 3

The molecular mechanisms of macrophages/microglia polarization and their functions.

Figure 4

miRNAs control macrophages/microglia polarization by regulating the signaling of key transcription factors. Multiple miRNAs can target the same transcription factor, and each miRNA can have a different target.