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(The FASEB Journal. 2004;18:1812-1817.)
© 2004 FASEB

Antagonism of RAGE suppresses peripheral nerve regeneration

LING LING RONG, WERNER TROJABORG, WU QU, KONSTANTIN KOSTOV, SHI DU YAN, CLIFTON GOOCH, MATTHIAS SZABOLCS, ARTHUR P. HAYS and ANN MARIE SCHMIDT1

Departments of Surgery, Neurology, Pathology, and Physiology & Cellular Biophysics, Columbia University Medical Center, New York, New York, USA

1Correspondence: Division of Surgical Science, Department of Surgery, Columbia University Medical Center, 630 W. 168th St., P&S 17-401, New York, NY 10032, USA. E-mail: ams11{at}columbia.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Axotomy of peripheral nerve triggers events that coordinate a limited inflammatory response to axonal degeneration and initiation of neurite outgrowth. Inflammatory and neurite outgrowth-promoting roles for the receptor for advanced glycation end products (RAGE) have been suggested, so we tested its role in peripheral nerve regeneration. Analysis of immunohistochemical localization of RAGE by confocal microscopy revealed that RAGE was expressed in axons and infiltrating mononuclear phagocytes upon unilateral sciatic nerve crush in mice. Administration of soluble RAGE, the extracellular ligand binding domain of RAGE, or blocking F(ab')2 fragments of antibodies raised to either RAGE or its ligands, S100/calgranulins or amphoterin, reduced functional recovery as assessed by motor and sensory nerve conduction velocities and sciatic functional index and reduced regeneration, as assessed by myelinated fiber density after acute crush of the sciatic nerve. In parallel, in mice subjected to RAGE blockade, decreased numbers of mononuclear phagocytes infiltrated the distal nerve segments after crush. These findings provide the first evidence of an innate function of the ligand/RAGE axis and suggest that RAGE plays an important role in regeneration of the peripheral nervous system.—Rong, L. L., Trojaborg, W., Qu, W., Kostov, K., Yan, S. D., Gooch, C., Szabolcs, M., Hays, A. P., Schmidt, A. M. Antagonism of RAGE suppresses peripheral nerve regeneration.


Key Words: inflammation • axonal regeneration • peripheral nervous system


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
EXPERIMENTAL AXOTOMY induced by nerve transection or crush activates an integrated series of cellular responses that mediate heightened, but limited inflammation and removal of myelin debris and damaged axonal elements distal to the site of injury. Injury also triggers sprouting and elongation of regenerating axons as they grow from the proximal nerve stump into the distal stump in an attempt to reinnervate target tissue and thus potentially restore function (1 2) .

The receptor for advanced glycation end products (RAGE) (3) has been linked to deleterious responses initiated by ligand-triggered cellular stress in diabetes, inflammation, neurodegeneration, and tumors (4 5 6 7 8) . In chronic diseases such as diabetes, sustained generation of RAGE ligands induces up-regulation of the receptor, leading to persistent cellular perturbation and irreparable tissue injury (9) . In the peripheral nerve, injury is followed by restoration of structure and eventual return of function. RAGE and its ligands, S100/calgranulins and amphoterin, share overlapping proinflammatory and neurite outgrowth-promoting properties and are expressed in nerve tissue (6 , 10 11 12 13 14 15 16 17) . We hypothesized that recruitment of the RAGE/ligand axis in acutely injured peripheral nerve might modulate the inflammatory response and neurite outgrowth which are essential for effective axonal regeneration after injury. We used pharmacological blockade of the receptor/ligand axis in a murine model and show that RAGE blockade attenuates effective regeneration after crush injury to the peripheral nerve.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal studies
All studies on mice were performed with the approval of the Institutional Animal Care and Use Committee of Columbia University, New York. This investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health. Male C57BL/6 mice (Jackson Laboratories, Bar Harbor, ME, USA) and mice with severe combined immunodeficiency (SCID; Taconic Farms, Germantown, NY, USA), age 3 months (n=15/group), maintained in a temperature-controlled room with alternating 12 h light-dark cycles were subjected to unilateral sciatic nerve crush. After induction of anesthesia by ketamine (100 mg/kg) and xylazine (10 mg/kg) diluted in phosphate-buffered saline (PBS) and administered by intraperitoneal (i.p.) injection, the left sciatic nerve was exposed from the sciatic notch to the trifurcation of the nerve. Four millimeters above the trifurcation, the nerve was crushed for 30 s twice with a Miltex 8-7 needle holder closed to the entire ratchet (width 1.5 mm) with a 90° rotation between each crush (18 19 20) .

Preparation and administration of soluble RAGE or antibodies raised against RAGE or its ligands
Murine soluble (s) RAGE was prepared in a baculovirus expression system and purified to homogeneity as described (5) . Soluble RAGE was devoid of any contaminating endotoxin by serial chromatography onto Detoxi-gel columns (Pierce, Arlington Heights, IL, USA) and sterile-filtered (0.2 µm) before administration. Mice were treated with sRAGE, 75 µg daily by i.p. route or murine serum albumin (100 µg/day) (Sigma, St. Louis, MO, USA) or PBS, beginning on the day of surgery until sacrifice. Murine sRAGE and murine serum albumin were diluted in PBS. In all cases, mice received 100 µL/day of the indicated treatment. Immunoglobulin (Ig) G of nonimmune rabbit, anti-RAGE, anti-amphoterin, or anti-S100/calgranulin were purified from rabbit serum using ImmunoPure A IgG purification kit (Pierce); F(ab')2 fragments were obtained from IgG with ImmunoPure F(ab')2 preparation kit (Pierce) according to the manufacturer’s instructions. SCID mice were treated with F(ab')2 fragments of nonimmune, anti-RAGE, anti-amphoterin, or anti-S100/calgranulin IgG (200 µg/0.2 mL/day) diluted in PBS beginning 6 h before surgery and continued every 3 days by i.p. injection until sacrifice.

Nerve conduction velocity
Twenty-one days after crush injury, mice were anesthetized with ketamine (100 mg/kg) and xylazine (10 mg/kg), diluted in PBS, and body temperature was kept constant at 37°C. A Nicolet Viking II computerized EMG system was used to stimulate and record all studies (Nicolet Biomedical, Madison, WI, USA). A square wave stimulus pulse (0.1 ms) at very low amperage (0–20 mA, average 4–5 mA) was delivered using a bipolar Nicolet Viking stimulator probe (Model S403) through attached subdermal needle electrodes (Nicolet Biomedical Disposable SS-Subdermal Needles). For motor studies, the sciatic nerve and its branches were stimulated at two sites, with recording from the same distal site for both stimulations. For proximal stimulation, the active electrode was placed in the superior dorsomedial upper thigh near midline at the sciatic notch, with the reference electrode 1 to 3 mm distally. For distal stimulation, the active electrode was placed in the vicinity of the medial knee, with the reference lateral. Evoked compound muscle action potentials (CMAPs) were recorded from the gastrocnemius muscle using needle recording electrodes (Medtronic, Inc., Tolochenaz, Switzerland) with the reference electrode in the ankle tendon. Amplitudes were measured in microvolts and the latency in milliseconds between stimulation and the CMAP onset was determined. Motor conduction velocity was calculated by dividing the distance between electrodes (measured with a fine caliper) by the difference in latency during stimulation at the sciatic notch compared with that obtained during knee stimulation to yield a velocity in meters/s. For sensory nerve conduction, the sural nerve was stimulated orthodromically using needle electrodes placed in the foot with recording via needle electrodes in the vicinity of the sciatic notch (as described for motor stimulation, above). Before recording, current was passed through the recording electrodes and the muscle response observed to insure proper placement of the electrodes proximate to the sciatic nerve. The sensory nerve action potential (SNAP) was recorded. SNAP amplitude was measured and the latency between stimulation and SNAP onset was measured. Sensory nerve conduction velocity was calculated by dividing the distance between the stimulating and recording electrodes (measured with fine caliper) by this latency.

Walking track analysis
Mice underwent preoperative, followed by postoperative walking track analysis on day 21 after nerve crush. Hind paws were immersed in bromophenol blue solution (Bio-Rad Laboratories, Hercules, CA, USA) and mice were allowed to walk freely along a corridor covered with white unmarked paper. Prints were selected from sites in which mice were walking at a stable, even, and moderate pace. Prints were obtained and scanned, captured, and measured by computer-assisted image analysis system. Sciatic functional indices were calculated according to published procedures (19) .

Histology
Mice were anesthetized and transcardially perfused with NaCl (0.9%), followed by paraformaldehyde (4%) in 0.1 M phosphate buffer (pH 7.4). Sciatic nerve segments from normal unlesioned mice or segments distal to the site of injury (the first 3 mm) from lesioned mice were removed and immersed in Tissue-Tek. Frozen sections (8 µm thick) were prepared 7 days after crush and fixed in acetone at –20°C, incubated with anti-F4/80 IgG (20 µg/mL) (Accurate Chemical, Westbury, NY, USA) for 18 h at 4°C, washed with 1x PBS for 5 min 5 times, followed by addition of alkaline phosphatase-conjugated goat anti-rat IgG (10 µg/mL) (Sigma), then developed on Fast Red substrate for conventional light microscopy. Immunohistochemistry of transverse sections was captured with a Zeiss microscope. Files were opened with Adobe Photoshop, then copied and saved as PICP files. Using NIH Image 1.62 software and highlighting of the stained areas, 4–10 different areas were measured. Background staining of each area was measured. Using control as baseline, fold induction was calculated. Nerves from 3–5 mice/group were stained and measured in this manner.

For confocal microscopy, freshly frozen sciatic nerves were cut to 5 µm in thickness. Sections were fixed in cold acetone at –20°C. Polyclonal rabbit anti-human RAGE IgG (11) , monoclonal anti-neurofilament IgG (Sigma), or monoclonal anti-human CD68 IgG (Dako, Glostrup, Denmark) (25, 20, and 15 µg/mL, respectively) were used as primary antibodies for confocal microscopy, followed by secondary antibody (Sigma) TRITC-conjugated goat anti-rabbit IgG (10 µg/mL) or FITC-conjugated goat anti-mouse IgG (5.5 µg/mL). Longitudinal sections were examined using a Zeiss LSM 410 confocal laser scanning microscope (Oberhocken, Germany). For light and electron microscopy, nerve segments were fixed in glutaraldehyde (2.5%; EM Science, Ft. Washington, PA, USA) and paraformaldehyde (2.0%) in PBS (0.1M; pH 7.4) at room temperature for 2–4 h and postfixed in osmium tetroxide (1%) for 1–1.5 h. Segments were serially dehydrated, and embedded in Spurr (EM Science). Semi-thin sections (0.5 µm) and thin sections (0.1 µm) were cut using a 2088 ultratome (LKB Produkter AB, Bromma, Sweden). Toluidine blue-stained semi-thin sections were examined under a Zeiss microscope. Images were captured using a CCD video camera connected to a computer image analysis system (Zeiss, Thornwood, NY, USA). Myelinated fibers on transverse sections were counted and fiber density was measured using Image Pro Plus software (MediaCybernetics, Silver Spring, MD, USA). Three sections per mouse in a group of 3–5 mice/condition were examined.

Statistical analysis
The mean ± SE is reported. Statistical comparisons among groups were determined using one-way ANOVA; where indicated, individual comparisons were performed using Students’ t test. Statistical significance was ascribed to the data when P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of RAGE in peripheral nerves subjected to acute injury
To test the hypothesis that recruitment of RAGE in injured peripheral nerve modulates the inflammatory response and neurite outgrowth, we examined receptor expression at baseline and after unilateral crush of the sciatic nerve in adult C57BL/6 male mice. At 18 h after injury, we studied segments within the first 3 mm distal to the site of crush. Before crush, confocal microscopy revealed expression of RAGE at baseline in axons as demonstrated by colocalization with anti-neurofilament IgG (Fig. 1 a–c). At 18 h after crush, RAGE was expressed in axons, as demonstrated by colocalization with anti-neurofilament IgG (Fig. 1d-f ), and in mononuclear phagocytes in the distal segments as shown by coexpression of immunoreactive RAGE and CD 68 (Fig. 1g-i ). These observations supported our hypothesis that RAGE was expressed in two key cell types linked to peripheral nerve regeneration: inflammatory mononuclear phagocytes and peripheral neurons.



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  		Figure 1. Expression of RAGE in sciatic nerve. Frozen sections (5 µm thick) of sciatic nerves were analyzed by confocal microscopy. Double staining for RAGE (a), neurofilament (b), and both (c) was performed on normal unlesioned C57BL/6J mouse sciatic nerve (longitudinal sections). Double staining for RAGE (d), neurofilament (e), and both (f); double staining for RAGE (g), CD68 (h), and both (i) were performed on the distal segments of sciatic nerves 18 h after crush injury on longitudinal sections. Representative sections for colocalization of RAGE with neurofilament or CD68 are illustrated. Scale bar: a–f) 36 µm; g–i) 35 µm.

Pharmacological blockade of RAGE suppresses nerve regeneration after sciatic nerve crush: the effects of soluble RAGE
Based on the finding that RAGE was expressed in key cell types in the injured peripheral nerve, we next sought to test the effect of pharmacological blockade of RAGE after nerve crush. We used distinct strategies to block the receptor. In our first studies, C57BL/6 mice subjected to sciatic nerve crush received sRAGE (5) . Soluble RAGE acts as a decoy to trap RAGE ligands and suppress their binding to and activation of cell surface receptor. Vehicle-treated animals received murine serum albumin (MSA) or PBS at the time of crush until sacrifice. Compared with either control treatment, sRAGE-treated animals displayed an ~60% decrease in motor and sensory nerve conduction velocities on day 21 after crush; P < 0.01 (Fig. 2 a, b). Conduction velocities in "normal" sciatic nerve (i.e., uninjured sciatic nerve) is shown for comparison (Fig. 2a, b ). In addition, sRAGE-treated mice displayed significantly impaired gait, measured as sciatic functional index, compared with MSA- or PBS-treated mice; P < 0.01 (Fig. 2c ).



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  		Figure 2. RAGE blockade suppresses nerve regeneration in mice subjected to sciatic nerve crush: effects of sRAGE. (a–c). On day 21 after crush injury, motor and sensory nerve conduction velocities (a, b) and sciatic functional index (c) were determined; n = 15/group. d–g) Immunohistochemistry for F4/80 (to detect macrophage epitopes) (anti-F4/80 IgG, 20 µg/mL) was performed on transverse frozen sections (8 µm thick) of distal segments from murine serum albumin- (MSA) (d), PBS- (e), or sRAGE-treated (f) mice on day 7 after crush injury. g) The extent of F4/80 immunoreactivity was quantified from n = 3 mice/group. Scale bar: d–f) 40 µm. h–o) On day 21 after crush, transverse distal segments of crushed sciatic nerve or unlesioned controls were embedded in Spurr and prepared for light microscopy (h–k, semi-thin sections, toluidine blue) or electron microscopy (l–n). o) Myelinated fiber density was determined from n = 3–5 mice/group. Scale bar: h–k) 100 µm; l–n) 2 µm.

The premise that inflammation and mononuclear phagocyte infiltration into the injured nerve is reduced by RAGE blockade is supported by decreased immunoreactivity for F4/80, a macrophage marker, in distal segments of sRAGE- vs. MSA- or PBS- treated nerve segments on day 7 after crush; P < 0.01 (Fig. 2d-g ).

Morphology in the distal 3 mm beyond the site of crush was examined in transverse semi-thin sections stained with toluidine blue (Fig. 2h-k ) and by electron microscopy (Fig. 2l-n ). In both cases, decreased numbers of myelinated fibers were evident in sRAGE-treated mice compared with control-treated animals. Consistent with these observations, quantitative analysis revealed an ~55% decrease in myelinated fiber density on day 21 after crush in sRAGE-treated animals vs. vehicle; P < 0.001 (Fig. 2o ).

Pharmacological blockade of RAGE and its ligands suppresses nerve regeneration after sciatic nerve crush: the effects of blocking antibodies to RAGE or its ligands
To directly antagonize RAGE and its ligands, we prepared F(ab')2 fragments from IgG raised against RAGE, amphoterin, or S100/calgranulin (6 7) . These antibodies or nonimmune F(ab')2 fragments prepared from rabbit IgG were administered by i.p. injection for 21 days to mice that had been subjected to nerve crush. As administration of such fragments for 3 wk would be expected to cause an immune response, we used adult mice with SCID. Compared with vehicle (PBS or nonimmune F(ab')2 fragments), mice receiving anti-RAGE, anti-S100/calgranulin, or anti-amphoterin F(ab')2 fragments displayed an ~42–63% decrease in motor and sensory nerve conduction velocities on day 21 after crush; P < 0.01 (Fig. 3 a, b). Functional recovery in SCID mice treated with receptor or ligand blockade, as assessed by sciatic functional index, was also decreased compared with vehicle-treated mice 21 days after nerve crush; P < 0.05. (Fig. 3c ). No significant differences in this index were observed between PBS- and nonimmune F(ab')2 fragment-treated SCID mice (Fig. 3c) .



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  		Figure 3. Ligand/RAGE blockade suppresses nerve regeneration in mice subjected to sciatic nerve crush: effects of blocking antibodies. a–c) SCID mice were subjected to sciatic nerve crush and the indicated treatments. On day 21, motor and sensory conduction velocities (a, b) and sciatic functional index (c) were determined. n = 15 mice/group. d–l) On day 21, transverse semi-thin sections of distal segments from the indicated groups were prepared for light microscopy (d–g, semi-thin sections, toluidine blue) or electron microscopy (h–k). l) Myelinated fiber density was determined from toluidine blue-stained semi-thin sections (n=3–5 mice/group). Scale bar: d–g) 100 µm; h–k) 3.5 µm.

Semi-thin sections (Fig. 3d-g ) and electron micrographs (Fig. 3h-k ) prepared from distal nerve segments after crush revealed decreased density of myelinated fibers in SCID mice treated with anti-receptor or ligand F(ab')2 fragments vs. nonimmune F(ab')2 fragments or PBS. Quantitative analysis of toluidine blue-stained transverse sections revealed an ~43–62% reduction in myelinated fiber density in anti-RAGE or anti-ligand F(ab')2 fragment-treated mice vs. vehicle on day 21 after crush (Fig. 3l ).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Axotomy in the peripheral nervous system initiates a cascade of overlapping, but integrated, inflammation-, and neurite outgrowth-promoting responses that rise, then recede as structure and function recover. Our findings indicate that RAGE blockade suppresses optimal regeneration in peripheral nerve subjected to acute crush injury. We propose that RAGE ligands actively engage RAGE on mononuclear phagocytes to initiate inflammatory mechanisms that trigger Wallerian degeneration and ready the distal stumps for optimal reception of the outgrowing axons. Consistent with this concept, numbers of mononuclear phagocytes infiltrating the distal nerve segments 7 days after crush were significantly reduced in sRAGE-treated mice. Further, expression of RAGE in axonal elements suggests that RAGE-dependent mechanisms may contribute to neurite outgrowth in response to acute crush. Myelinated fiber density was reduced in RAGE/ligand-blocked animals after crush, suggesting that regenerative mechanisms were suppressed. Although it is possible these effects resulted solely from diminished Wallerian degeneration by RAGE blockade, we propose that studies suggesting a significant role for RAGE in cellular migration of tumor and smooth muscle cells may be extended to outgrowing peripheral neurites after crush injury in the adult peripheral nervous system (7 , 21) . The confocal microscopy findings presented here do not exclude RAGE expression in Schwann cells. In fact, it is likely that RAGE is expressed by these cells, particularly after injury. Rapid reprogramming of Schwann cells after injury initiates breakdown and removal of myelin shed from degenerating axons. It is postulated that Schwann cells may assume mononuclear phagocyte-like properties upon injury (22 23) . Cellular functions are rapidly diverted from a differentiated state to one in which phagocytosis and myelin clearance pave the way to optimal outgrowth and reception of regenerating axons.

These findings provide evidence for innate roles for RAGE in the response to injury and show for the first time that blockade of RAGE may impair reparative responses. Although RAGE ligands, including S100/calgranulins and amphoterin expressed by multiple cell types, have traditionally been linked to deleterious inflammatory responses when expressed in the extracellular milieu (15 , 24 25) , here endogenous functions of these molecules have been uncovered in the physiologic response to acute nerve crush. Previous experiments showed that blocking antibodies to S100/calgranulins or amphoterin reduced inflammation in delayed-type hypersensitivity reactions or massive endotoxemia, respectively (6 , 25) ; the present studies reveal that administration of blocking antibodies to RAGE ligands attenuated regeneration. It is important to note that mice with SCID do display regeneration after sciatic nerve crush: assessment of conduction velocities, sciatic functional index, and myelinated fiber density after crush revealed results comparable to those observed in vehicle-treated C57BL/6 mice after crush.

In addition to stimulation of proinflammatory mechanisms, the biologic impact of S100/calgranulins and amphoterin is likely also linked to neurite outgrowth-promoting properties, as evidence for roles of each of these classes of molecules in neurite outgrowth has been published, at least in the in vitro setting (11 12 , 14 , 26) . In the developing nervous system, amphoterin was found to mediate neurite outgrowth of embryonic neurites at least in part via RAGE ligation (11) . Our findings thus highlight novel roles for RAGE and its ligands in response to acute injury. In chronic disease; however, evidence suggests that sustained up-regulation of this axis leads to long-term injury and failure of regeneration.

These findings stand in stark contrast to the beneficial roles of RAGE blockade in chronic diseases such as diabetes, where administration of RAGE antagonists facilitated wound repair and attenuated vascular inflammation in diabetic mice (27 28) . For this reason, the role of RAGE blockade in diabetic neuropathy and in acute nerve injury in diabetes must be addressed. It has been shown that in mice rendered diabetic with streptozotocin, sciatic nerve transection was associated with diminished number and caliber of regenerated myelinated fibers (29) . In those studies, although macrophage invasion into injured nerve stumps was delayed, once initiated, resorption of inflammatory cells was slowed. Once triggered, injured diabetic nerve thus is susceptible to sustained activation of proinflammatory mechanisms, leading to failure of reparative pathways. Roles for RAGE in diabetic neuropathy are certainly plausible, as other RAGE ligands—specifically, AGEs—accumulate in chronic diabetic nerve secondary to hyperglycemia and oxidant stress.

Taken together, these data suggest that acute crush in adult nerve tissue recruits RAGE-dependent mechanisms, thereby initiating processes that contribute to repair. These observations uncover for the first time innate roles for RAGE in the biologic response to injury in the adult peripheral nervous system.


   ACKNOWLEDGMENTS
 
This work was supported in part by the Surgical Research Fund of the Columbia University Medical Center, and by grants from the U.S. Public Health Service. A.M.S. is a recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

Received for publication March 17, 2004. Accepted for publication August 5, 2004.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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