Fig. 2

From injury to scar: time course of progressive scar pathology showing interlinked relationships between different components of the spinal injury scar. Following traumatic spinal cord injury, acute cell death and damage triggers release of cell-derived and blood-derived DAMPs, ATP release, dysregulated ionic homeostasis oxidative stress and excitotoxicity, which represent potent stimuli for triggering glial cell activation, stromal cell proliferation, deposition of extracellular matrix (ECM), and recruitment of circulating innate immune cells. Within a few days following injury, monocyte-derived macrophage/microglia adopt a predominantly M1 phenotype which do not favour resolution and tissue remodelling becomes fibrotic. Proinflammatory innate responders also present DAMP-derived antigens (such as MBP) to T and B-cells. B cells, in turn, may present antigens to T-cells, triggering their expansion. During this time, reactive astrocytes proliferate, hypertrophy and overlap in order to isolate this zone of non-resolving pathology from spared tissue. They also secrete matrix CSPGs, which are known to downregulate neuronal plasticity. Wallerian degeneration of degenerating axonal tracts contributes to continued deposition of axonal and myelin debris, which is ineffectively processed by immune cells and leads to the deposition of myelin-associated molecules (MAG, Nogo, OMgp) which are known inhibitors of neuronal regrowth. Ongoing Wallerian degeneration at later post-injury stages further triggers gliosis and neuroinflammation. Dashed grey arrows show cross talk between different components of the spinal injury scar, which is usually bidirectional. For example, CSPGs released by reactive astrocytes are thought to activate receptors on macrophages/microglia to induce a proinflammatory phenotype and in turn increasing inflammation induces further astrocytic reactivity and CSPG deposition. Fibroblast-like cells also synthesise type 1 collagen, implicated in the induction of astrogliosis and further deposition of matrix molecules. Cross talk between the innate and adaptive immune response also propagates inflammatory pathology and further influences glial activation and CSPG production. The dynamic interactions between inflammation, dramatic tissue and ECM remodelling and reactive cellular and extracellular changes drive the progressive, propagating pathology that culminates in the spinal injury scar