Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

Abstract

Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focuses of SCI therapeutic research. Within and around the glial scar, cells deposit extracellular matrix (ECM) proteins that affect axon growth such as chondroitin sulfate proteoglycans (CSPGs), laminin, collagen, and fibronectin. This dense deposition of material, i.e., the fibrotic scar, is another barrier to endogenous repair and is a target of SCI therapies. Infiltrating neutrophils and monocytes are recruited to the injury site through glial chemokine and cytokine release and subsequent upregulation of chemotactic cellular adhesion molecules and selectins on endothelial cells. These peripheral immune cells, along with endogenous microglia, drive a robust inflammatory response to injury with heterogeneous reparative and pathological properties and are targeted for therapeutic modification. Here, we review the role of glial and inflammatory cells after SCI and the therapeutic strategies that aim to replace, dampen, or alter their activity to modulate SCI scarring and inflammation and improve injury outcomes.

Keywords: Macrophage; azithromycin; chondroitinase ABC (chABC); glial limitans; human; traumatic brain injury..

Fig. 1

Schematic of resident and infiltrating glial cells and associated therapies following traumatic spinal cord injury. Resident microglia and astrocytes are activated following injury and form a glial scar surrounding and sequestering the damaged tissue (top). Fibroblasts and inflammatory cells infiltrate into the damaged tissue and deposit extracellular matrix proteins forming the fibrous scar (middle). Activated cells exacerbate damage, leading to an expanded secondary injury. Therapeutic approaches (bold) and example agents (hyphenated) targeting glial activation, scar formation, and inflammation after spinal cord injury (bottom). This therapeutic list is not comprehensive, and references and abbreviations are in the main body of the manuscript