Abstract:Peripheral nerve injury induces endoneural inflammation, controlled by diverse cytokines and extracellular mediators. Although inflammation is coupled to axonal regeneration, fulminant inflammation may increase nerve damage and neuropathic pain. a 2 -Macroglobulin (a2M) is a plasma protease inhibitor, cytokine carrier, and ligand for cell-signaling receptors, which exists in two well-characterized conformations and in less well-characterized intermediate states. Previously, we generated an a2M derivative (a 2 … Show more
Tumor necrosis factor-alpha (TNF-α) is a principal mediator in pro-inflammatory processes that involve necrosis, apoptosis and proliferation. Experimental and clinical evidence demonstrate that peripheral nerve injury results in activation and morphological changes of microglial cells in the spinal cord. These adjustments occur in order to initiate an inflammatory cascade in response to the damage. Between the agents involved in this reaction, TNF-α is recognized as a key player in this process as it not only modulates lesion formation, but also because it is suggested to induce nociceptive signals. Nowadays, even though the function of TNF-α in inflammation and pain production seems to be generally accepted, diverse sources of literature point to different pathways and outcomes. In this review, we systematically searched and reviewed original articles from the past 10 years on animal models of peripheral nervous injury describing TNF-α expression in neural tissue and pain behavior.
Tumor necrosis factor-alpha (TNF-α) is a principal mediator in pro-inflammatory processes that involve necrosis, apoptosis and proliferation. Experimental and clinical evidence demonstrate that peripheral nerve injury results in activation and morphological changes of microglial cells in the spinal cord. These adjustments occur in order to initiate an inflammatory cascade in response to the damage. Between the agents involved in this reaction, TNF-α is recognized as a key player in this process as it not only modulates lesion formation, but also because it is suggested to induce nociceptive signals. Nowadays, even though the function of TNF-α in inflammation and pain production seems to be generally accepted, diverse sources of literature point to different pathways and outcomes. In this review, we systematically searched and reviewed original articles from the past 10 years on animal models of peripheral nervous injury describing TNF-α expression in neural tissue and pain behavior.
“…Taken together, our previous and current results suggest that in the absence of added reagents, Schwann cells may establish autocrine cell-signaling pathways involving endogenously-produced LRP-1 ligands that control Akt activation. Many LRP-1 ligands have been previously shown to regulate the response to PNS injury (Boyles et al, 1989; Arandjelovic et al, 2007, Sachs et al, 2007); however, not all LRP-1 ligands stimulate cell-signaling, as evidenced by the lack of response to RAP. Understanding LRP-1-dependent and –independent pathways by which proteins that bind to LRP-1 function in the injured PNS is a goal for future investigation.…”
Low density lipoprotein receptor-related protein (LRP-1) is an endocytic receptor for diverse proteins, including matrix metalloproteinase-9 (MMP-9), and a cell-signaling receptor. In the peripheral nervous system (PNS), LRP-1 is robustly expressed by Schwann cells only after injury. Herein, we demonstrate that MMP-9 activates extracellular-signal regulated kinase (ERK1/2) and Akt in Schwann cells in culture. MMP-9 also promotes Schwann cell migration. These activities require LRP-1. MMP-9-induced cell-signaling and migration were blocked by inhibiting MMP-9-binding to LRP-1 with receptor-associated protein (RAP) or by LRP-1 gene-silencing. The effects of MMP-9 on Schwann cell migration also were inhibited by blocking the cell-signaling response. An antibody targeting the hemopexin domain of MMP-9, which mediates the interaction with LRP-1, blocked MMP-9-induced cell signaling and migration. Furthermore, a novel GST-fusion protein (MMP-9-PEX), which includes only the hemopexin domain of MMP-9, replicated the activities of intact MMP-9, activating Schwann cell-signaling and migration by an LRP-1-dependent pathway. Constitutively-active MEK1 promoted Schwann cell migration; in these cells, MMP-9-PEX had no further effect, indicating that ERK1/2 activation is sufficient to explain the effects of MMP-9-PEX on Schwann cell migration. Injection of MMP-9-PEX into sciatic nerves, 24 h after crush injury, robustly increased phosphorylation of ERK1/2 and Akt. This response was inhibited by RAP. MMP-9-PEX failed to activate cell-signaling in uninjured nerves, consistent with the observation that Schwann cells express LRP-1 at significant levels only after nerve injury. These results establish LRP-1 as a cell-signaling receptor for MMP-9, which may be significant in regulating Schwann cell migration and physiology in PNS injury.
“…Extracellular chaperones, such as clusterin, have been shown to protect cells from a range of stresses . Clusterin and α 2 m have both been shown to protect cells from Aβ toxicity (Boggs et al 1996;Fabrizi et al 2001) and TNFα-mediated cell death (Humphreys et al 1997;Arandjelovic et al 2007). α 2 m can also protect cells by binding to and trapping proteases (Ikari et al 2001).…”
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