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Review
. 2014 Aug:258:24-34.
doi: 10.1016/j.expneurol.2013.11.020.

Extracellular matrix regulation of inflammation in the healthy and injured spinal cord

Andrew D Gaudet  1 , Phillip G Popovich  2
Affiliations
Review

Extracellular matrix regulation of inflammation in the healthy and injured spinal cord

Andrew D Gaudet et al. Exp Neurol. 2014 Aug.

Abstract

Throughout the body, the extracellular matrix (ECM) provides structure and organization to tissues and also helps regulate cell migration and intercellular communication. In the injured spinal cord (or brain), changes in the composition and structure of the ECM undoubtedly contribute to regeneration failure. Less appreciated is how the native and injured ECM influences intraspinal inflammation and, conversely, how neuroinflammation affects the synthesis and deposition of ECM after CNS injury. In all tissues, inflammation can be initiated and propagated by ECM disruption. Molecules of ECM newly liberated by injury or inflammation include hyaluronan fragments, tenascins, and sulfated proteoglycans. These act as "damage-associated molecular patterns" or "alarmins", i.e., endogenous proteins that trigger and subsequently amplify inflammation. Activated inflammatory cells, in turn, further damage the ECM by releasing degradative enzymes including matrix metalloproteinases (MMPs). After spinal cord injury (SCI), destabilization or alteration of the structural and chemical compositions of the ECM affects migration, communication, and survival of all cells - neural and non-neural - that are critical for spinal cord repair. By stabilizing ECM structure or modifying their ability to trigger the degradative effects of inflammation, it may be possible to create an environment that is more conducive to tissue repair and axon plasticity after SCI.

Keywords: DAMP; Hyaluronan; Immune; Neuroinflammation; Proteoglycan; TLR; Tenascin; Toll-like receptors.

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Figures

Figure 1
Figure 1
Limited research publications exist with a focus on understanding the interactions between inflammation, the SCI, and ECM (red area). Searches were performed on PubMed for the words “inflammation”, “spinal cord injury”, and “extracellular matrix”, alone and in combination (as of September 2013). “Inflammation” returned ~418 000 results; “spinal cord injury” ~50 000, and “extracellular matrix” ~80 000. However, when a search combined all three terms, only 19 results were returned. Sizes of circles and overlaps are proportional to the total number of citations returned for each search (Venn diagram constructed using eulerAPE). In the context of SCI and its relationship to inflammation and the ECM, vast expanses of knowledge remain to be discovered.
Figure 2
Figure 2
(a) Major interstitial ECM components in the healthy CNS. The massive non-sulfated GAG hyaluronan (HA) is the most prominent structural component of CNS ECM. Aggrecan (CS/KSPG) and tenascin-R are also enriched in healthy ECM. The three types of PGs are hyaluronan-binding hyalectans, small leucine-rich repeat proteins (SLRPs), and cell surface PGs. GAGs (including HA) are green and are shown attached to thicker core proteins (shades of blue). The N-terminal of the hyalectans aggrecan, versican, neurocan, and brevican bind to HA with assistance from link proteins (pink circles). Small leucine-rich repeat proteins (SLRPs) exist in the extracellular space and participate in important protein-protein interactions. Cell surface PGs contain transmembrane domains or can be GPI-linked to the membrane. Some cell-surface PGs can also be released extracellularly by proteolytic processing (not shown). CD44 containing the v3 domain can bind HS or CS GAG (shown). The ECM protein tenascin-R, which exists as a dimer or trimer, can bind a lectin-like domain on the C-terminal of hyalectans. The HA-hyalectan-tenascin interactions likely underlie ECM scaffold development and maintenance in CNS ECM. Size of molecules in image approximates actual relative size (except HA, which is much longer than depicted) and GAG chain composition. Schematic is not representative of the relative abundance of these molecules in healthy CNS. Tenascin-C (grey) is not highly expressed in the healthy CNS; however, it is important after SCI. Small grey lines on cell surface PGs represent intramolecular disulfide bonds. (b) Model of ECM molecular interactions that contribute to scaffolding and structure adult CNS, before injury (left) and after injury (right). Massive HMW-HA GAG chains fill space and provide binding sites for hyalectans. The CS/DSPG aggrecan is particularly enriched in the healthy CNS, and forms large aggregates on HA GAGs. Tenascin-R interaction with lectin-like domains on hyalectans could link neighboring HA-based aggregates, creating defined 3D structure and organization of the CNS interstitial ECM. Hyalectans can also exist unbound to HA. After SCI, CNS ECM composition is changed, and its meshwork structure is fragmented. HMW-HA, which is normally ~2000 kDa, is degraded into LMW-HA (<200 kDa). As the most critical structural CNS ECM component, HA degradation causes catastrophic ECM breakdown. Aggrecan is downregulated/degraded after injury; the other hyalectans (brevican, versican, neurocan) are strongly upregulated for weeks after SCI. Hexameric tenascin-C is aberrantly expressed after SCI and could create new or different molecular interactions, and change steric configurations. SLRPs and the matrix-modifying MMPs are upregulated during inflammation. Size of molecules approximates actual scale.
Figure 3
Figure 3
SCI-induced changes in ECM composition and release of proinflammatory mediators contribute to a viscous feed-forward cycle exacerbates ECM degradation and inflammation. SCI causes degradation or nascent expression of various ECM molecules. Some of these newly-created ECM molecules act as DAMPs and can activate ECM receptors (including TLRs, integrins, CD44, and RPTPs); others can bind cytokines, chemokines, or growth factors to modulate their presentation to inflammatory cells. Activation of ECM receptors or chemokine/cytokine/growth factor receptors on leukocytes (or astrocytes and microglia) can elicit pro-inflammatory mediator secretion and migration of these cells. Accumulation of activated inflammatory cells contributes to secretion of pro-inflammatory mediators (which are also increased by other SCI-induced mechanisms, like primary trauma and hemorrhagic necrosis). Secreted pro-inflammatory mediators further modify and degrade ECM molecules.
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