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Review
. 2019 Aug;76(16):3141-3156.
doi: 10.1007/s00018-019-03176-4. Epub 2019 Jun 6.

Matrix metalloproteinase signals following neurotrauma are right on cue

Alpa Trivedi  1 , Linda J Noble-Haeusslein  2 , Jonathan M Levine  3 , Alison D Santucci  4 , Thomas M Reeves  5 , Linda L Phillips  5
Affiliations
Review

Matrix metalloproteinase signals following neurotrauma are right on cue

Alpa Trivedi et al. Cell Mol Life Sci. 2019 Aug.

Abstract

Neurotrauma, a term referencing both traumatic brain and spinal cord injuries, is unique to neurodegeneration in that onset is clearly defined. From the perspective of matrix metalloproteinases (MMPs), there is opportunity to define their temporal participation in injury and recovery beginning at the level of the synapse. Here we examine the diverse roles of MMPs in the context of targeted insults (optic nerve lesion and hippocampal and olfactory bulb deafferentation), and clinically relevant focal models of traumatic brain and spinal cord injuries. Time-specific MMP postinjury signaling is critical to synaptic recovery after focal axonal injuries; members of the MMP family exhibit a signature temporal profile corresponding to axonal degeneration and regrowth, where they direct postinjury reorganization and synaptic stabilization. In both traumatic brain and spinal cord injuries, MMPs mediate early secondary pathogenesis including disruption of the blood-brain barrier, creating an environment that may be hostile to recovery. They are also critical players in wound healing including angiogenesis and the formation of an inhibitory glial scar. Experimental strategies to reduce their activity in the acute phase result in long-term neurological recovery after neurotrauma and have led to the first clinical trial in spinal cord injured pet dogs.

Keywords: Angiogenesis; Axonal plasticity; Deafferentation; Neuroinflammation; SCI; TBI.

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Figures

Fig. 1
Fig. 1
Postinjury MMP protein and mRNA expression following optic nerve lesion. Rodent MMP expression after either optic nerve crush or transection insult. X-axis shows degeneration/regeneration time course. A 5–7-d increase in MMP protein levels (left panel) is matched by transcript elevation during early degeneration (right panel). Each MMP protein exhibits a different temporal pattern: MMP-9 increases earlier than MMP-2, whose activity maps concurrently; MMP-1 is biphasic, rising with degeneration and regeneration. MMP-3 is restricted to early regeneration. Transcript induction for each MMP is high into the regenerative phase, returning to control baseline over time. This time-dependent MMP response suggests cued role(s) to facilitate regeneration 1[4]; 2[6]; 3[7]
Fig. 2
Fig. 2
Postinjury MMP response in hippocampus and olfactory bulb following deafferentation. a Rodent MMP expression after entorhinal cortical lesion (ECL) deafferentation. X-axis shows degeneration/regeneration time course. MMP-3 transcript and protein increase acutely, in tandem with membrane-type MT5-MMP and ADAM10 protein (left panel). MMP-3 remains elevated throughout synapse regeneration, while the membrane-type enzymes return to baseline with synapse maturation at 15 d. Inducible activity of pro-enzyme is similarly elevated 1–2 d postlesion, with MMP-9 rapidly reduced by 7 d (right panel). By contrast, ADAMTS activity is below baseline at 1–2 d, but peaks at 7-d onset of terminal sprouting. The hippocampus shows time-dependent MMP response during reactive synaptogenesis. MMPs are prominent during acute degeneration and during the onset of synapse regeneration 1[1]; 2[10]; 3[26]; 4[13]; 5[12]. b Rodent MMP expression after olfactory bulb deafferentation (nerve transection [TX] or sensory neuron nasal chemical lesion [CL]). X-axis shows degeneration/regeneration time course. Rapid acute MMP-9 upregulation, peaks in degenerative phase, with a delayed MMP-2 induction at onset of synaptic repair. Nerve transection vs. sensory neuron lesion exhibits different response. MMP-9 rise is delayed after chemical lesion and peaks much higher. MMP-2 shows the opposite temporal pattern, where chemical lesion produces a modest 5-d peak relative vs. > 5X rise at 10-d rise with nerve transection. Olfactory bulb shows a time-dependent MMP response with deafferentation-induced synaptic plasticity and illustrates how injury modality alters cued MMP response 1[15]; 2[14]; 3[17]
Fig. 3
Fig. 3
Summary of the temporal pattern of blood–brain barrier (BBB) disruption after spinal cord injury, relative to the expression of MMPs. Note the prominent leakage that occurs immediately after the injury, which likely reflects direct damage to the neurovascular unit (NVU). This is followed by a second phase of permeability, which peaks by about 2–3 d postinjury, with a reduction in permeability thereafter, corresponding to the angiogenic phase. The mechanism(s) driving extended permeability beyond about a month has yet to be identified
Fig. 4
Fig. 4
Role of MMP-2 and MMP-9 on angiogenesis is time and context dependent. MMP-2 modulates endothelial proliferation and tube formation, whereas MMP-9 transiently supports only the latter. However, prolonged exposure to MMP-9 leads to pericyte detachment and vascular regression. Data represented from [69]. Image adapted from [105]
Fig. 5
Fig. 5
Effect of maladaptive plasticity on metalloproteinase response and functional outcome. a Paired metalloproteinase and substrate data showing exacerbated MMP-3/ADAM10 response with maladaptive combined fluid percussion injury and entorhinal cortical lesion (FPI + ECL) vs. adaptive ECL. Maladaptive increase in metalloproteinase expression (mRNA or protein) attenuates Agrin and N-cadherin level at the onset of reinnervation (7 d) and synapse maturation (15 d). Acute postinjury MMP inhibition reverses both reversal of cognitive deficits (b) and restores capacity for LTP induction (c) in the maladaptive FPI + ECL model. d Working model of MMP interaction with signaling proteins LCN2 and OPN to affect glial mediation of synaptic plasticity. Infiltrating leukocytes secrete LCN2 and OPN, which are processed by MMPs to activate local glia (left box). These glia can release leukocyte chemoattractant MCP-1 (blue) to enhance infiltration. MMP/signal protein amplification can further mediate cell response during acute degeneration and synapse regeneration (right boxes). GF growth factor. Data in a–c are taken from [11, 13, 26]
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