Macrophage centripetal migration drives spontaneous healing process after spinal cord injury

Abstract

Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury.

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

“…M2 macrophages may also enhance the polarization of reactive astrocytes after SCI (Sonn et al, 2019). Inhibition of the centripetal migration of macrophages impairs the migration of astrocytes and glial scar formation, resulting in exacerbated neuronal loss and decreased functional recovery (Kobayakawa et al, 2019). However, excessive macrophage activity also contributes to damaging cascade reactions, secondary damage and axonal dieback (Evans et al, 2014).…”

Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury

“…Both the CNS cells in the neurovascular unit and blood-borne peripheral cells constantly modulate the BSCB and influence its breakdown and repair after SCI [ 11 ], however, a significant amount of research in the past few years has focused on the effects of astrocytes and pericytes on BSCB homeostasis, yet the role of macrophages/microglia in the BSCB has been seldom defined. Current data indicate that a large number of peripheral macrophages will enter the injured spinal cord and trigger a cascade of responses after SCI [ 12 ]. It was showed that macrophages have two polarization states including “classically-activated”, proinflammatory, cytotoxic M1 phenotype and “alternatively-activated”, anti-inflammatory, pro-repair M2 phenotype [ 13 ].…”

Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis

“…In spite of their therapeutic potential, there are some obvious disadvantages associated to the use of MSCs in the treatment of SCI. Specifically, the survival rate of the transplanted stem cells is very low due to severe inflammatory responses or other factors in the injured microenvironment [ 10 – 12 ]. Additionally, the scar-forming gliosis prevents the integration, differentiation, and axon outgrowth of grafted stem cells in the lesion area [ 13 , 14 ].…”