Wallerian degeneration even though it did not encounter the physical trauma directly. Among others, axons break down, Schwann cells reject the myelin portion ...
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Waddell Signs ▶ Nonorganic Symptoms and Signs
Wage Replacement Definition
The medication used to confer epidural analgesia typically causes lower extremity motor weakness. With the “walking epidural” technique, a small concentration of local anesthetic with an opioid is used to achieve analgesia while maintaining lower extremity motor function. There is no scientific evidence demonstrating a benefit with respect to obstetric outcome, but women are more satisfied when they can move their legs during labor.
The wage replacement benefit is the ratio of the expected disability benefit to the preinjury wage.
Cross-References Cross-References
▶ Analgesia During Labor and Delivery
▶ Pain in the Workplace, Risk Factors for Chronicity, and Workplace Factors
Wallerian Degeneration Wage Replacement Benefit ▶ Worker Compensation Benefits
Shlomo Rotshenker Department of Medical Neurobiology, IMRIC, Faculty of Medicine Hebrew University of Jerusalem, Jerusalem, Israel
Walking Epidural
Synonyms
Definition
Cytokines, upregulation in inflammation neuropathic pain model, chronic constriction injury; Dorsal root ganglionectomy and dorsal rhizotomy; Neuropathic pain model, diabetic neuropathy model; Painless neuropathies
“Walking epidural” is a term used to describe an epidural technique whereby a woman in labor has analgesia but is also able to ambulate.
G.F. Gebhart, R.F. Schmidt (eds.), Encyclopedia of Pain, DOI 10.1007/978-3-642-28753-4, # Springer-Verlag Berlin Heidelberg 2013
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Wallerian Degeneration
Definition
from ruptured vasculature rapidly accumulate at the lesion site. Then, the nerve stump that is located distal to the lesion site undergoes Wallerian degeneration even though it did not encounter the physical trauma directly. Among others, axons break down, Schwann cells reject the myelin portion of their membranes and proliferate, fibroblasts proliferate, and bone-marrow-derived monocytes/macrophages are recruited from the circulation. Recruitment begins on the second day after the injury, but macrophages reach significant numbers as of the fourth day after the injury. Activated macrophages and Schwann cells complete the removal of degenerated myelin by phagocytosis within 8–12 days. The clearance of the degenerated myelin is essential for successful regeneration and restoration of function since myelin contains molecules which inhibit the growth of severed adult axons. The simplistic view that Wallerian degeneration emanates from the loss of metabolic support of axons due to disconnection from their cell bodies is at most partial since in mutant Wlds mice axon/myelin degeneration, monocytes/macrophages recruitment, and myelin clearance are delayed for many days after the injury. The finding of the aberrant molecule that is composed of the N-terminal 70 amino acid of the multiubiquitination factor Ube4b fused to NAD+-synthesizing enzyme Nmnat1 in Wlds mice led to the notion that isoform(s) of Nmnat, which are produced in neuronal cell bodies and transported anterogradely, protects axons by inhibiting a self-destructing mechanism (Gilley and Coleman 2010; Avery et al. 2009; Sasaki et al. 2009). Taken together, Wlds mice display abnormal slow progression of Wallerian degeneration compared to the normal faster progression of Wallerian degeneration that wild-type mice display as described above (Brown et al. 1991; Reichert et al. 1994). Wallerian degeneration in wild-type mice will be referred to as Wallerian degeneration or “normal Wallerian degeneration,” and Wallerian degeneration in Wlds mice will be referred to as “slow Wallerian degeneration.”
▶ Wallerian degeneration, named after Waller (1850), defines the array of cellular and molecular events that follow a traumatic injury to PNS (peripheral nervous system) ▶ axons. Wallerian degeneration takes place throughout the nerve segment situated distal to a lesion site: anterograde degeneration.
Introduction Wallerian degeneration can be viewed as the inflammatory, innate immune response of the PNS to traumatic injury. The production of cytokines, the mediator molecules of inflammation; the involvement of monocytes/macrophages, which are inflammatory/innate immune cells; and the phagocytosis of degenerated myelin, which is an innate immune function, indicate this. The term Wallerian degeneration is sometimes used in reference to a traumatic injury to CNS (central nervous system) axons even though cell types, cellular events, and outcomes differ substantially. The term Wallerian degeneration is also occasionally used to define events that develop during PNS neuropathies without trauma but those that differ from injury-induced Wallerian degeneration. The term Wallerian degeneration that is used here refers to injuryinduced Wallerian degeneration in the PNS.
Characteristics Cellular Characteristics of Wallerian Degeneration In intact PNS (Fig. 1a), ▶ Schwann cells surround axons and form myelin sheaths around the larger diameter sensory and motor axons. In between nerve fibers, ▶ fibroblasts and a few mast cells and macrophages are scattered. Endothelial cells are present within walls of capillaries that nourish the PNS tissue. Traumatic injury produces immediate tissue damage at the lesion site where physical impact occurred (Fig. 1b). Monocytes/macrophages that originate
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Wallerian Degeneration, Fig. 1 Intact (A) and injured (B) PNS. (A) Intact axons are surrounded by myelinforming Schwann cells, and fibroblasts are scattered between nerve fibers. (B) Traumatic injury produces immediate tissue damage at lesion sites where macrophages accumulate. Normal Wallerian degeneration then develops throughout distal to lesion sites. Among others, axons degenerate, Schwann cells reject their myelin,
macrophages are recruited, and macrophages and Schwann cells are activated to phagocytose myelin. In complete PNS injury, all axons undergo normal Wallerian degeneration. In partial PNS injury, lesioned axons and nonneuronal cells participating in Wallerian degeneration are situated next to intact axons and their associated nonneuronal cells and receptors (envisage axons A and B next to each other)
The Cytokine Network of Wallerian Degeneration Detailed examinations of cytokine-mRNA expression and cytokine-protein synthesis and secretion in wild-type mice that display normal Wallerian degeneration indicate that cytokine production is orchestrated in time and magnitude, thereby forming the cytokine network of Wallerian degeneration (Fig. 2) (Rotshenker et al. 1992; Reichert et al. 1996; Saada et al. 1996; Be’eri et al. 1998; Shamash et al. 2002; Mirski et al. 2003; Rotshenker 2011). The producing nonneuronal cell types, their spatial distribution in the PNS tissue, and the timing of monocyte/macrophage recruitment determine timing and magnitude. Schwann cells are the first to respond rapidly to axotomy by producing the inflammatory cytokines TNFa followed by IL-1a. The rapid
response of Schwann cells is possible since (1) they form intimate contact with axons and are thus the first among the nonneuronal cells to “sense” axonal injury, (2) they normally express TNFa and IL-1a mRNAs, and (3) they normally contain low levels of TNFa protein. Fibroblasts follow by producing IL-6 and GM-CSF within 2 and 4 h after the injury, respectively. IL-6 and GM-CSF production can be induced by diffusible TNFa and IL-1a synthesized and secreted by Schwann cells. IL-1b, whose onset of production by Schwann cells is delayed by 5–10 h after the injury, can further contribute to IL-6 and GM-CSF production. Schwann cell-derived TNFa, IL-1a, and IL-1b advance monocyte/macrophage recruitment directly and indirectly by inducing the production of MCP-1 (chemoattractant protein-1, known also as CCL2, (C-C motif ligand 2) and
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Wallerian Degeneration
Wallerian Degeneration, Fig. 2 The cytokine network of Wallerian degeneration. The cellular elements depicted are a resident Schwann cell surrounding an axon, a resident fibroblast, endothelial cells forming the wall of a capillary containing circulating monocytes, and a recruited macrophage that acquired the M2 phenotype. Solid and dotted lines, respectively, represent up- and downregulation of cytokines’ protein production, and the curved line represents the transmigration of a recruited monocyte/macrophage. Axotomy induces the production of TNFa and IL-1a in resident Schwann cells first. Sequentially thereafter follow IL-6 and GM-CSF production in resident fibroblasts and IL-1 b production in resident Schwann cells. Schwann cells, fibroblasts, and endothelial cells further produce chemokines MCP-1a
and MIP-1a which advance monocyte/macrophage recruitment. Apo-E (apolipoprotein-E) and Gal-3 (Galectin-3) drive recruited monocytes/macrophages to differentiate into the M2 phenotype which produces high levels of IL-10 and IL-6 but low levels of TNFa, IL-1a, and IL-1 b. The anti-inflammatory cytokine IL-10 downregulates the production of all inflammatory cytokines and itself in all nonneuronal cells. Schwann cells and fibroblasts also produce the neurotrophic factors NGF and LIF. Not shown are the breakdown of the axon and the myelin, the phagocytosis of the degenerated myelin, and the additional cellular and molecular interactions that are detailed in text (After Shamash et al. 2002; Rotshenker 2011)
MIP-1a (macrophage inflammatory protein-1a, known also as CCL3) in Schwann cells, fibroblasts, mast cells, and endothelial cells. MCP-1/CCL2 and MIP-1a/CCL3 then promote the transmigration of circulating monocytes across the endothelial cell wall of blood vessels (Subang and Richardson 2001; Perrin et al. 2005). Concomitantly, Schwann cell-derived TNFa, IL-1a, and IL-1b induce recruited monocytes/macrophages to synthesize high levels of IL-6 but low levels of TNFa, IL-1a, and IL-1b.
Schwann cell-derived TNFa, IL-1a, and IL-1b further induce the production of the anti-inflammatory cytokine IL-10 in fibroblasts and the recruited monocytes/macrophages (Be’eri et al. 1998; Rotshenker 2011). Indeed, the onset of IL-10 production by fibroblasts is rapid, but levels of production are low and insignificant. High levels of IL-10 are produced by, and therefore concomitant with, monocyte/macrophage recruitment from the fourth day of Wallerian degeneration. IL-10 then downregulates the production of the inflammatory cytokines and
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itself, thereby downregulating the inflammatory aspects of Wallerian degeneration. IL-6, which macrophages also produce, contributes to the downregulation of TNFa production. Remarkably, all cytokines augment myelin phagocytosis by macrophages. The inflammatory nature of Wallerian degeneration and the role of cytokines are supported by observations of deficient cytokine production during slow Wallerian degeneration in mutant Wlds mice. Notably, TNFa and IL-1a protein production fails in slow Wallerian degeneration in Wlds mice even though their mRNAs are expressed, which suggests differential regulation between mRNA expression and protein synthesis. It is likely, therefore, that Schwann cell-derived TNFa and IL-1a play a critical role in setting the normal cytokine network and normal Wallerian degeneration in motion, and the failure of their production results in an abnormal deficient cytokine network and slow Wallerian degeneration. Of note, production levels of TNFa, IL-1a, and IL-1b peak on the first day following the injury prior to monocyte/macrophage recruitment, and, furthermore, production levels decrease as recruited monocytes/macrophages increase in number (Shamash et al. 2002; Rotshenker 2011). Taken that recruited macrophages produce high levels of the anti-inflammatory cytokine IL-10 but low levels of the inflammatory cytokines TNFa, IL-1a, and IL-1b strongly suggests that these macrophages are of the M2 “wound healing” phenotype (Auffray et al. 2009; Benoit et al. 2008). This is in contrast to high-level production of inflammatory but low-level production of antiinflammatory cytokines by macrophages of the M1 phenotype. Nonetheless, both M1 and M2 macrophages function as phagocytes. Immune Inhibitory Receptors in Wallerian Degeneration Innate immune functions are regulated by the interplay between activating and inhibitory signals; neither act in an “all or none” fashion. Inhibition is produced by a family of immune inhibitory receptors. SIRPa
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(signal-regulatory-protein-a, known also as CD172a and SHPS1) is a member of this family (Barclay and Brown 2006; Matozaki et al. 2009). SIRPa is expressed on the surface of macrophages and microglia. Its ligand is the cell membrane protein receptor CD47 (known also as IAP – integrin-associated protein) that many cells express on their surface. Cells that express CD47 can downregulate their own phagocytosis by macrophages after CD47 binds and activates SIRPa on phagocytes. CD47 functions, therefore, as a marker of “self” that protects cells from activated autologous macrophages by sending a “do not eat me” signal. CD47 is expressed on myelin and the myelin-forming Schwann cells and oligodendrocytes, and, furthermore, myelin downregulates its own phagocytosis by macrophages and microglia through CD47-SIRPa interactions (Gitik et al. 2011). CD47 can function, therefore, as a marker of “self” that protects intact myelin and Schwann cells from activated macrophages in the PNS. This mechanism may be useful under normal conditions and while combating invading pathogens since it protects bystander intact myelin and myelin-forming cells from macrophages that are activated to scavenge and kill pathogens. However, the very same mechanism may turn harmful when faster removal of degenerated myelin is useful as after traumatic PNS injury. Therefore, it is most likely that normal Wallerian degeneration does not display the fastest possible rate of in vivo myelin clearance. Neurotrophic Factors in Wallerian Degeneration ▶ Neurotrophic factors are an additional class of molecules whose expression is altered after PNS injury (reviewed in Terenghi 1999). For example, NGF (▶ Nerve Growth Factor), BDNF (brain-derived neurotrophic factor), NT-4 (neurotrophin-4), GDNF (glial-derived neurotrophic factor), and LIF (leukemia inhibitory factor) expressions are upregulated in normal Wallerian degeneration. In contrast, CNTF (ciliary neurotrophic factor) and NT-3 expressions are downregulated in normal Wallerian degeneration.
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Cytokines and neurotrophic factors are closely associated. For example, NGF production upregulation is integrated into the cytokine network of Wallerian degeneration. NGF mRNA expression and protein synthesis is efficient in normal Wallerian degeneration but deficient in slow Wallerian degeneration (Brown et al. 1991). This discrepancy can be partially explained by the following: (1) the efficient versus deficient TNFa, IL-1a, and IL-1b production in normal and slow Wallerian degeneration, respectively (see above), and (2) the induction of NGF production in fibroblasts by these cytokines (Hattori et al. 1994). Furthermore, some molecules display both neurotrophic factor and cytokine properties, for example, IL-6, LIF, and CNTF (Patterson 1994; Stahl and Yancopoulos 1994). Neuropathic Pain and Wallerian Degeneration Delayed and reduced neuropathic pain in Wlds mice that display slow Wallerian degeneration (Myers et al. 1996) and the ability to provoke neuropathic pain by inducing inflammation without axonal injury (Safieh-Garabedian et al. 1995; Woolf et al. 1997; Eliav et al. 2001) suggest that the molecular events associated with Wallerian degeneration play a major role in the development of neuropathic inflammatory pain (e.g., IL1b, TNFa, and NGF). There are several potential sites of action for molecules produced in Wallerian degeneration. First, secreted/diffusible molecules may act upon the producing and neighboring nonneuronal cells in an autocrine/paracrine fashion. For example, TNFa and IL-1a secreted from Schwann cells may induce productions, among others, of IL-6, GM-CSF, MCP-1/ CCL-2, and NGF in nearby fibroblasts (Fig. 2). Second, in instances of partial PNS injury, some axons are cut but others remain intact (Fig. 1; envisage axons A and B next to each other). Molecules (e.g., TNFa and NGF) secreted from the nonneuronal cells that participate in Wallerian degeneration may affect the neighboring intact axons, myelinated and non-myelinated; their surrounding Schwann cells and sensory
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receptors/endings to alter electrical properties and thresholds; and the mechanisms suggested to be instrumental in the pathophysiology of neuropathic pain (Wu et al. 2002). Third, at the neuroma site, the region immediately proximal to the injury site (
