Inflammation and Spinal Cord Injury: Infiltrating Leukocytes as Determinants of Injury and Repair Processes

Abstract

The immune response that accompanies spinal cord injury contributes to both injury and reparative processes. It is this duality that is the focus of this review. Here we consider the complex cellular and molecular immune responses that lead to the infiltration of leukocytes and glial activation, promote oxidative stress and tissue damage, influence wound healing, and subsequently modulate locomotor recovery. Immunomodulatory strategies to improve outcomes are gaining momentum as ongoing research carefully dissects those pathways, which likely mediate cell injury from those, which favor recovery processes. Current therapeutic strategies address divergent approaches including early immunoblockade and vaccination with immune cells to prevent early tissue damage and support a wound-healing environment that favors plasticity. Despite these advances, there remain basic questions regarding how inflammatory cells interact in the injured spinal cord. Such questions likely arise as a result of our limited understanding of immune cell/neural interactions in a dynamic environment that culminates in progressive cell injury, demyelination, and regenerative failure.

Figure 1. Characterization of immunity

In general, cells associated with innate immunity are either tissue specific or derived from a circulating pool of inflammatory cells. The adaptive response consists of both humoral and cellular components. The humoral response is typified by the production of antibodies and is mediated by B-lymphocytes. The cellular response is mediated by T-lymphocytes, which are further classified into cytotoxic, CD8⁺ and helper cells, CD4⁺. CD4⁺ cells give rise to either TH1 or TH2 types of responses. TH1 cells produce pro-inflammatory cytokines such as IFN-γ, TNF-agr;, and IL-6, whereas TH2 cells secrete anti-inflammatory cytokines including IL-4, IL-10 and TGF-β. Abbreviations: Interferon-gamma - IFN-γ; tumor necrosis factor-alpha - TNF-agr;; interleukin-6 - IL-6; interleukin-4 - IL-4; interleukin-10 - IL-10; and transforming growth factor-beta - TGF-β.

Figure 2. Schematic representation of timing of infiltration of inflammatory cells relative to secondary pathogenesis and wound healing

Inflammatory cells participate in both early tissue injury and in wound healing events. This summarizes data from several studies that have addressed the timing of infiltration relative to early injury and wound healing events. Peak periods of infiltration coincide with barrier disruption ^{(91, 92)}, angiogenesis ^(–95), and glial scar formation ⁽¹¹⁾. Note that the magnitude of infiltration is expressed as arbitrary units for each of the cell types, and as such comparisons cannot be made between groups.