Glial-Neuronal Interactions in Pathogenesis and Treatment of Spinal Cord Injury

Abstract

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macrophages and microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs. anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlights the time-dependent transformation of reactive microglia and astrocytes into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide suggestions on how to modulate the inflammation and discuss key therapeutic approaches leading to better functional outcome after SCI.

Mechanism Underlying Acupuncture Therapy in Spinal Cord Injury: A Narrative Overview of Preclinical Studies

“…SCI is a dynamic pathological process causing nerve cell and nerve fiber edema at the initial stages, followed by microcirculation disorders due to damaged blood cells ( Rivlin and Tator, 1978 ; Tator and Fehlings, 1991 ). Then, the nerve cell axons degenerate or die and are gradually replaced by glial cells ( O’Shea et al, 2017 ; Lukacova et al, 2021 ). Aggravation of cellular, molecular, and other factors at different stages post SCI leads to a series of pathophysiological changes, reducing the spinal cord functional recovery ( Tator, 1995 ).…”

The immune microenvironment and tissue engineering strategies for spinal cord regeneration

“…However, scarring largely prevents neuron regeneration and differentiation. The mechanical barrier of axonal regeneration includes a variety of cells (astrocytes, oligodendrocyte progenitor cells, immune cells fibroblasts) and cell matrix compositions ( Bradbury and Burnside, 2019 ; Lukacova et al, 2021 ). Activated astrocytes also have two different phenotypes, namely, A1 and A2, similar to macrophages.…”

Emerging Roles of Microglia Depletion in the Treatment of Spinal Cord Injury

“…M2a and M2c are regarded as the major neuroprotective cell types of microglia, which can effectively limit secondary inflammation-mediated tissue damage and promote spinal cord repair. Moreover, the expression of the aforementioned neuroprotective markers of M2a and M2c were positively correlated with neurological outcome after SCI, especially at the early-stage post-injury [ 45 , 46 ].…”