Inflammogenesis of Secondary Spinal Cord Injury

Abstract

Spinal cord injury (SCI) and spinal infarction lead to neurological complications and eventually to paraplegia or quadriplegia. These extremely debilitating conditions are major contributors to morbidity. Our understanding of SCI has certainly increased during the last decade, but remains far from clear. SCI consists of two defined phases: the initial impact causes primary injury, which is followed by a prolonged secondary injury consisting of evolving sub-phases that may last for years. The underlying pathophysiological mechanisms driving this condition are complex. Derangement of the vasculature is a notable feature of the pathology of SCI. In particular, an important component of SCI is the ischemia-reperfusion injury (IRI) that leads to endothelial dysfunction and changes in vascular permeability. Indeed, together with endothelial cell damage and failure in homeostasis, ischemia reperfusion injury triggers full-blown inflammatory cascades arising from activation of residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (neutrophils and macrophages). These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit. Therefore, our review considers the recent advances in SCI mechanisms, whereby it becomes clear that SCI is a heterogeneous condition. Hence, this leads towards evidence of a restorative approach based on monotherapy with multiple targets or combinatorial treatment. Moreover, from evaluation of the existing literature, it appears that there is an urgent requirement for multi-centered, randomized trials for a large patient population. These clinical studies would offer an opportunity in stratifying SCI patients at high risk and selecting appropriate, optimal therapeutic regimens for personalized medicine.

Keywords: glia; inflammation; ischemia-reperfusion injury (IRI); leukocytes; reactive oxygen species (ROS); spinal cord injury (SCI); therapeutics.

Figure 1

An overview of rat models of Spinal cord injury (SCI). The principle site of injury is the dorsal thoracic spine, and the dorsal spinal artery.

Figure 2

Inflammatory milieu produced by secondary injury. An increase in vascular permeability is initiated by hemorrhaging. This is then followed by extravasation of activated leukocytes, which release inflammatory ligands (such as MMPs to degrade extracellular matrix and intercellular proteins). Interaction between ferrous iron (Fe²⁺) and hydrogen peroxide yields hydroxyl radicals (Fenton reaction). Ferric iron (Fe³⁺) reacts with superoxide to produce oxygen (Haber-Weiss reaction). Reactive oxygen species (ROS) activates proteins with cysteine-rich residues by structural modification (oxidation, nitration), and to induce multiple signaling pathways that also modulate gene expression. Intracellular levels of anti-oxidants are depleted in reducing Fe³⁺ to Fe²⁺ state. Ultimately, the free radicals lead to cell and tissue damage, resulting in neuronal and glial necrosis and apoptosis in SC parenchyma. In contrast, beneficial effects are mediated through subsets of leukocytes and glial cells, which play a crucial role in anti-inflammatory mechanisms.

Figure 3

Synopsis of microglia phenotypes (M1 and M2), the two ends of the biological spectrum. Inflammatory cytokines (IL-1β, IL-6, IL-12, IFN-γ, TNF-α), anti-inflammatory cytokines (IL-4, IL-10, IL-13, TGF-β), chemokines (CCL2, CXCL1, CX3CL1), growth factors (IGF, insulin-like growth factor; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; CNF, ciliary neurotrophic factor; EGF, epidermal growth factor), SP, substance P; NO, nitric oxide; ROS, reactive oxygen species; ${\text{O}}_2^{•-}$, superoxide; CGRP, calcitonin gene-related peptide; LPS, lipopolysaccharide; ATP, adenosine triphosphate; Resolvin D1, lipid mediator derived from docosahexaenoic acid. Also, asterocytes display similar phenotypic polarization.

Figure 4

Schematic illustration displaying primary (cavitation) and secondary lesions, neuronal necrosis, axonal destruction and demyelination during secondary injury with parenchymal resident cells (reactive astrocytes, microglia), and extravasation of peripheral leukocytes (neutrophils, monocytes/macrophages, and lymphocytes: B,T and natural killer cells). Wallerian degeneration (microtubules disassembly, microtubule associated protein degradation by calcium-dependent neutral protease calpain, blebbing of axons, fragmentation and phagocytosis by microglia and macrophages). A small quantity of Schwann cells are present in CNS, and also they migrate to the CNS from the peripheral nervous system.

Figure 5

Simplified diagram exhibiting the major components of the complement cascade, including regulators of complement activation and pathophysiological effects.