Immune response following traumatic spinal cord injury: Pathophysiology and therapies

Abstract

Traumatic spinal cord injury (SCI) is a devastating condition that is often associated with significant loss of function and/or permanent disability. The pathophysiology of SCI is complex and occurs in two phases. First, the mechanical damage from the trauma causes immediate acute cell dysfunction and cell death. Then, secondary mechanisms of injury further propagate the cell dysfunction and cell death over the course of days, weeks, or even months. Among the secondary injury mechanisms, inflammation has been shown to be a key determinant of the secondary injury severity and significantly worsens cell death and functional outcomes. Thus, in addition to surgical management of SCI, selectively targeting the immune response following SCI could substantially decrease the progression of secondary injury and improve patient outcomes. In order to develop such therapies, a detailed molecular understanding of the timing of the immune response following SCI is necessary. Recently, several studies have mapped the cytokine/chemokine and cell proliferation patterns following SCI. In this review, we examine the immune response underlying the pathophysiology of SCI and assess both current and future therapies including pharmaceutical therapies, stem cell therapy, and the exciting potential of extracellular vesicle therapy.

Keywords: SCI; extracellular vesicle; neuroimmunology; stem cell; tSCI therapies; traumatic spinal cord injury; vesicle.

Figure 1

Mechanisms of secondary injury following traumatic spinal cord injury. Several key secondary mechanisms of injury that have been shown to contribute to the propagation of acute cell dysfunction and cell death including ischemia/hypoxia, neuroinflammation, vascular disruption/edema, lipid peroxidation, oxidative stress, cell death, ionic imbalance, formation of a glial scar, glial activation, and matrix remodeling are depicted. Following SCI, three zones that differ in tissue quality form including: (1) Zone 1, which is mainly a product of the initial trauma and is defined by regions of necrosis, inflammation, and cysts; (2) Zone 2, is characterized by regions of incomplete injury that are still accompanied by immune cell infiltration, axonal swelling, and Wallerian degeneration; and (3) Zone 3, which are histologically intact areas (15, 16).

Figure 2

Patterns of immune cell infiltration following spinal cord injury. The order and timing (, –31) of various immune cell infiltrates is depicted (32). The level of neutrophils peak at approximately 24 hours after SCI and decrease over the course of the next 7-10 days. Comparatively, lymphocytes peak much later and at lower levels compared to neutrophils. The resident macrophages, microglia, are early responders after SCI. Eventually, microglia become indistinguishable from the peripherally derived macrophages from a morphological standpoint.