Toll-like receptor 2 contributes to chemokine gene expression and macrophage infiltration in the dorsal root ganglia after peripheral nerve injury
© Kim et al; licensee BioMed Central Ltd. 2011
Received: 22 April 2011
Accepted: 28 September 2011
Published: 28 September 2011
We have previously reported that nerve injury-induced neuropathic pain is attenuated in toll-like receptor 2 (TLR2) knock-out mice. In these mice, inflammatory gene expression and spinal cord microglia actvation is compromised, whereas the effects in the dorsal root ganglia (DRG) have not been tested. In this study, we investigated the role of TLR2 in inflammatory responses in the DRG after peripheral nerve injury.
L5 spinal nerve transection injury induced the expression of macrophage-attracting chemokines such as CCL2/MCP-1 and CCL3/MIP-1 and subsequent macrophage infiltration in the DRG of wild-type mice. In TLR2 knock-out mice, however, the induction of chemokine expression and macrophage infiltration following nerve injury were markedly reduced. Similarly, the induction of IL-1β and TNF-α expression in the DRG by spinal nerve injury was ameliorated in TLR2 knock-out mice. The reduced inflammatory response in the DRG was accompanied by attenuation of nerve injury-induced spontaneous pain hypersensitivity in TLR2 knock-out mice.
Our data show that TLR2 contributes to nerve injury-induced proinflammatory chemokine/cytokine gene expression and macrophage infiltration in the DRG, which may have relevance in the reduced pain hypersensitivity in TLR2 knock-out mice after spinal nerve injury.
A series of studies have demonstrated that activation of spinal cord glial cells plays an important role in the development of neuropathic pain after peripheral nerve injury . Activation of spinal cord glia in the absence of peripheral nerve injury enhanced pain sensitivity , and inhibition of these cells attenuated pain behavior in a neuropathic pain model [3, 4]. Non-neuronal cells in the dorsal root ganglia (DRG) have also been implicated in the development of nerve injury-induced neuropathic pain . Upon peripheral nerve injury, Schwann cells are activated and produce proinflammatory cytokines such as TNF-α and IL-1β [6, 7]. In addition, peripheral immune cells including macrophages and neutrophils are activated and infiltrate into DRG after peripheral nerve injury [8–10]. Along with this immune cell infiltration, various proinflammatory cytokines and chemokines, including TNF-α, IL-1β, and MCP-1, are expressed in the DRG of injured nerves after peripheral nerve injury [11, 12]. It has been suggested that expression of these proinflammatory cytokines and chemokines may sensitize primary afferent sensory neurons in the DRG [13–15]. Thus, it is conceivable that macrophage infiltration into the DRG may contribute to the development of pain hypersensitivity after peripheral nerve injury. However, the exact role of the infiltrating macrophages in pain induction and the mechanism of macrophage infiltration into the injured DRG have not been clearly elucidated.
Toll-like receptors (TLRs) are pattern-recognition receptors that recognize pathogen-associated molecular patterns. In mammals, TLRs detect infectious agents and trigger an innate immune response in the host organism . Furthermore, certain TLRs recognize endogenous molecules that are released from damaged cells and tissues, suggesting that TLRs may also function as receptors detecting cell/tissue damage in the body [17, 18]. It has been suggested that TLR2, TLR3, and TLR4 play a role in the initiation of neuropathic pain through the recognition of host-derived endogenous ligands [19–21]. Based on these reports, it was hypothesized that TLR endogenous ligands released from the damaged sensory neurons might activate spinal cord glial cells and thereby enhance pain hypersensitivity. Moreover, it was recently reported that TLR2 and TLR4 signaling induces macrophage activation and infiltration into injured sciatic nerves and regulates Wallerian degeneration . These data suggest that TLR may also regulate nerve injury-induced macrophage infiltration into the DRG and thereby affect pain hypersensitivity. In this study, we explored this hypothesis using TLR2 knock-out mice and found that TLR2 facilitates macrophage infiltration and pain-mediating proinflammatory gene expression in the DRG after spinal nerve injury.
Macrophages infiltrate into the DRG after peripheral nerve injury
TLR2 contributes to macrophage infiltration in the DRG after peripheral nerve injury
Peripheral nerve injury-induced expressions of CCL2/MCP-1 and CCL3/MIP-1α in the DRG are reduced in TLR2 knock-out mice
Chemokine gene expression in DRGs after L5 spinal nerve injury.
20.9 ± 3.6*
8.0 ± 1.6*
0.7 ± 0.3
5.8 ± 0.5**
0.6 ± 0.2
7.0 ± 0.9*
4.2 ± 0.2**
0.8 ± 0.0
2.2 ± 0.4*
1.1 ± 0.3
4.1 ± 0.2**
4.1 ± 0.5*
2.5 ± 0.2*
2.7 ± 0.1**
2.9 ± 0.6
TLR2 contributes to peripheral nerve injury-induced TNF-α and IL-1β expression in the DRG and to the development of spontaneous pain behavior
Previous studies have shown that TNF-α is expressed in neurons and satellite cells in the DRG after nerve injury . We have also detected TNF-α expression in a subset of DRG neurons after spinal nerve transection (data not shown). However, the cells that express IL-1β in the DRG after peripheral nerve injury have not been identified. In this study, we found that the IL-1β-expressing cells co-stained mainly with CD68-IR macrophages in WT DRG at 7 days after spinal nerve injury (Figure 5C), indicating expression of IL-1β by macrophages. The reduced expressions of these cytokines in the DRG of the L5 spinal nerve-injured TLR2 knock-out mice were accompanied by a reduction of nerve injury-induced spontaneous pain as assessed by foot lifting behavior (Figure 5D). At 14 days after peripheral nerve injury, the duration of spontaneous foot lifting during a 5-min period increased to 20 sec in WT mice, whereas it was attenuated by more than 50% in TLR2 knock-out mice (Figure 5D). Collectively, these data show that expression of TNF-α and IL-1β is reduced in the DRG of nerve injured-TLR2 knock-out mice compared with WT mice, which may be relevant in the reduction of nerve injury-induced spontaneous pain hypersensitivity observed in the TLR2 knock-out mice.
Neuropathic pain often develops following peripheral nerve damage. In this pathological condition, peripheral immune cells including macrophages and T cells infiltrate into the damaged peripheral nerve  and the adjacent DRG [8, 9, 32]. At the same time, proinflammatory cytokines and chemokines are upregulated in the DRG associated with the injured nerves . However, the mechanisms underlying this nerve injury-induced macrophage infiltration and proinflammatory cytokine/chemokine induction in the DRG have not yet been elucidated. In the present study, we demonstrated that TLR2 plays important roles in nerve injury-induced macrophage infiltration in the DRG after peripheral nerve injury. We also found increased expression of several chemokines, including CCL2/MCP-1 and CCL3/MIP-1α, in the DRG of injured WT mice, whereas this expression was attenuated in TLR2 knock-out mice. The difference in the expression levels of macrophage-attracting chemokines after nerve injury between WT and TLR2 knock-out mice may account for the decreased macrophage infiltration in the TLR2 knock-out DRG. Previous studies have shown that CCL2/MCP-1 is expressed in DRG sensory neurons after peripheral nerve injury [27, 34]. In accordance with these reports, we demonstrated CCL2/MCP-1 expression in DRG neurons of injured nerves; in fact, among the chemokines expressed in the DRG, CCL2/MCP-1 was the most significantly upregulated after nerve injury at early time points. This finding raised the possibility that TLR2 expressed in injured DRG neurons may directly regulate CCL2/MCP-1 expression in this cell type. This is consistent with a previous report showing TLR4 expression in the sensory neurons of rat trigeminal ganglia . However, in our immunohistochemical studies we failed to detect TLR2 expression in any of the DRG neurons; instead, we observed TLR2 expression in GFAP+ satellite glia and Iba-1+ macrophages in the DRG. Based on these data, we reasoned that TLR2-expressing satellite glial cells or macrophages in the DRG might respond to nerve injury and indirectly induce CCL2/MCP-1 expression in DRG neurons after peripheral nerve injury, thus enhancing macrophage infiltration.
It is not clear how TLR2 expressed on satellite glial cells and macrophages in the DRG recognizes or responds to peripheral nerve injury. Although purely speculative, it can be conjectured that certain TLR2 endogenous ligand(s) are released from the damaged DRG neurons after spinal nerve injury, which in turn activate TLR2 on nearby satellite glial cells or macrophages. To date, several endogenous TLR agonists have been reported; for example, TLR2 and TLR4 recognize molecules released from damaged cells/tissues including heat shock proteins, HMGB-1, and hyaluronic acid, and thereby transmit a "danger signal" in the innate immune cells [17, 18]. In addition, TLR3 is known to bind to mRNA released from necrotic cells . Therefore, it will be interesting to test whether any of these endogenous TLR agonists are released in the DRG after peripheral nerve injury. In line with these reports, it is notable that all of these TLR members are implicated in nerve injury-induced pain hypersensitivity [19–21].
We previously showed that nerve injury-induced activation of spinal cord microglia and subsequent pain hypersensitivity is attenuated in TLR2 knock-out mice, suggesting a putative role of microglial TLR2 in nerve injury-induced neuropathic pain. The data from this study suggest that TLR2 on satellite glial cells and macrophages in the DRG may also be involved in nerve injury-induced pain hypersensitivity. At present, it is not clear whether microglial TLR2 and TLR2 on DRG cells (macrophages and/or satellite glia) contribute independently to nerve injury-induced pain hypersensitivity. Moreover, the relative contribution of these two cell populations to pain induction has not been elucidated. Of note, there is a slight difference in the kinetics of cell activation and infiltration in the spinal cord and DRG after nerve injury; DRG infiltration of macrophages after nerve injury peaks at 7 dpi, whereas nerve injury-induced spinal cord microglia activation peaks at 4 dpi . Considering this, we think it is less likely that TLR2-mediated macrophage infiltration in the DRG affects the rate of spinal cord microglia activation after spinal nerve injury. Recently, Shi et al. argued that TLR2-mediated macrophage infiltration in injured nerves plays a critical role in the development of neuropathic pain . They contended that the effects of TLR2 on microglia activation are minimal based on their observation of a similar level of spinal cord microglia activation in WT vs. TLR2 knock-out mice after nerve injury. In this study, however, they measured spinal cord microglia activation only at 14 dpi, at which point nerve injury-induced spinal cord microglia activation largely subsides . In contrast, we observed a significant difference in spinal cord microglia activation in TLR2 knock-out mice compared to WT mice at 4 and 7 dpi . Additionally, Shi et al. showed that macrophage infiltration in injured nerves peaks at 14 dpi . In contrast, in our study macrophage infiltration in the DRG peaked at 7 dpi, whereas the infiltration rate at 3 dpi and 14 dpi was comparable (Figure 1B). Such differences in the kinetics of macrophage infiltration suggest that it is less likely that TLR2 effects on the DRG are secondary to their effects on injured nerves.
In addition to its role in nerve injury-induced mechanical allodynia and thermal hyperalgesia , in this study we report for the first time that TLR2 is also involved in spontaneous pain induction after nerve injury. Spontaneous pain may arise as a result of ectopic action potential generation within the neuronal cell body of the damaged DRG and/or neuroma . Interestingly, many studies have demonstrated that proinflammatory cytokines and chemokines can directly activate or sensitize pain-mediating sensory neurons in the DRG. For example, CCL-2/MCP-1 increases the excitability of nociceptive neurons by transactivating TRPV1 channels . CXCL-1 has also been shown to regulate excitability of DRG neurons by regulating their sodium and potassium currents [40, 41]. Likewise, excitatory effects of TNF-α and IL-1β on nociceptive DRG neurons have been reported [13, 14]. These previous reports suggest that the expression of these cytokines/chemokines in the DRG after peripheral nerve injury may activate or sensitize nociceptive neurons in the DRG and thereby induce pain hypersensitivity. Thus, our study, in conjuction with a study by Shi et. al. , suggests that the attenuated induction of spontaneous pain observed in TLR2 knock-out mice may be attributed to the decreased expression of proinflammatory genes in the DRG or injured nerve. Of interest, we also detected macrophage infiltration in L4 DRGs after L5 nerve injury, although the infiltration rate was much lower than that for L5 DRG (data not shown). This suggests the possibility that macrophage infiltration into non-injured DRG may affect neuropathic pain induction, a hypothesis which was not further investigated in this study.
In conclusion, our study demonstrates that TLR2 contributes to macrophage infiltration and proinflammatory cytokine/chemokine gene expression in the DRG of injured nerves after spinal nerve injury. These data illustrate putative mechanisms underlying nerve injury-induced immune cell infiltration and proinflammatory cytokine/chemokine expression in the DRG.
Animals and Surgery
All animal experiments were performed in male mice ranging in age from 8 to 10 weeks and weighing 20 to 25 g. All mice were housed in an animal facility with a specific pathogen-free barrier at a temperature of 23°C. They experienced a 12-h light-dark cycle and were fed food and water ad libitum. TLR2 knock-out mice that had been backcrossed to C57BL/6 background for more than 10 generations were obtained from Dr. S. Akira (Osaka University, Japan); C57BL/6 mice (Orient Bio, South Korea) were used as WT control. The L5 spinal nerve was transected as previously described  with minor modification. We anesthetized animals with sodium pentobarbital (50 mg/kg, i.p.) and removed the L6 transverse process to identify the L4 and L5 spinal nerves. The L5 spinal nerve was then isolated and transected. The wound was irrigated with saline and closed with surgical skin staples. All animal experimental procedures were performed according to guidelines from the International Association for the Study of Pain (IASP) and were approved by the Institutional Animal Care and Use Committee (IACUC) of Seoul National University.
Spontaneous pain was measured using spontaneous foot lifting behavior following L5 spinal nerve transection, as previously described . Following L5 spinal nerve injury, mice were placed under a transparent plastic cover (15 cm × 15 cm) and adapted for 20 min. After adaptation, the duration of spontaneous foot lifting was measured for 5 min. Foot lifts associated with locomotion or repositioning of the body were not counted. Average scores were recorded in duplicate trials. The behavioral tests were performed in a blinded fashion.
Primers used for real-time RT-PCR.
5'-AGG TCA TCC CAG AGC TGA ACG-3'
5'-CAC CCT GTT GCT GTA GCC GTA T-3'
5'-TAA TGA CTC TGC GTT TGC CCT G-3'
5'-ATT GGA GCT GCC CAC AAT GAG-3'
5'-AGC AAA CCA CCA AGT GGA GGA-3'
5'-GCT GGC ACC ACT AGT TGG TTG T-3'
5'-TTG TGG CTG TGG AGA AGC TGT-3'
5'-AAC GTC ACA CAC CAG CAG GTT-3'
5'-TCA GCC AGA TGC AGT TAA CG-3'
5'-GAT CCT CTT GTA GCT CTC CAG C-3'
5'-ACT GCC TGC TGC TTC TCC TAC A-3'
5'-AGG AAA ATG ACA CCT GGC TGG-3'
5'-CTC ACC ATC ATC CTC ACT GCA-3'
5'-GCA CTT GCT GCT GGT GTA GAA A-3'
5'-CAC ACT CAA GAA TGG TCG CGA-3'
5'-TTG TCA GAA GCC AGC GTT CAC-3'
5'-TGC CGT CAT TTT CTG CCT CA-3'
5'-TCA CTG GCC CGT CAT CGA TAT-3'
Mice were deeply anesthetized with sodium pentobarbital (50 mg/kg) and then sacrificed by transcardial perfusion with 4% paraformaldehyde in 0.1 M phosphate buffer at either 1, 3, 7, or 14 days after surgery. The DRGs associated with injured nerves were removed by laminectomy, post-fixed at 4°C overnight, and then transferred to 30% sucrose in PBS for 48 h. Transverse sections (10 μm thick) of DRGs were prepared on gelatin-coated glass slides using a cryocut microtome (Leica CM3050S, Germany). The slides were blocked in solution containing 5% normal donkey serum, 2% bovine serum albumin, and 0.1% Triton X-100 for 1 h at room temperature (RT), incubated overnight at 4°C with rabbit anti-Iba-1 antibody (1:2,000, Wako, Japan) [44, 45] or rat anti-CD68 antibody (1:500, Serotec, Oxford, UK) [46, 47] for macrophage staining, and finally incubated with goat anti-CCL2/MCP-1 antibody (1:200, R&D Systems, Minneapolis, MN, USA) , mouse anti-NeuN antibody (1:1000, Chemicon, Temecula, CA, USA), mouse anti-TLR2 antibody (1:100, eBioscience, San Diego, CA, USA), rabbit anti-MAP2 antibody (1:2,000, Millipore, Bedford, MA, USA), rabbit anti-GFAP antibody (1:10,000, DAKO, Glostrup, Denmark) [49, 50], and goat anti-IL-1β antibody (1:100, R&D Systems) . The sections were then incubated for 1 h at RT with a mixture of FITC-conjugated and Cy3-conjugated secondary antibodies (1:200, Jackson ImmunoResearch, Bar Harbor, ME, USA). The sections were mounted on slides using Vectashield mounting medium (Vector Laboratories, Burlingame, CA, USA) and fluorescent images were obtained with a confocal microscope (LSM 5 Pascal, Carl Zeiss, Germany). At each time point, L5 DRGs were prepared from more than three WT and TLR2 knock-out mice. Three sections per DRG were stained, and three fields (100 μm × 100 μm) were selected in each stained DRG section. The intensities of Iba-1 and CD68 staining were quantified using ImageJ software (NIH Image, Bethesda, MD, USA) as described elsewhere .
Enzyme-linked immunsorbant assay (ELISA)
DRG tissues were collected from WT and TLR2 knock-out mice after L5 spinal nerve transection or a sham operation. Tissue lysates were prepared from the DRGs using a micro tissue grinder (Wheaton, Millville, NJ, USA) in 200 μl RIPA buffer (50 mM Tris-HCl, 150 mM NaCl, 1% SDS, 1% Nonidet P-40, 0.5% sodium deoxycholate, 20 mM EGTA) containing protease inhibitors (Calbiochem, La Jolla, CA, USA). The DRG lysates were centrifuged at 12,000 rpm for 5 min to remove tissue debris; the total protein concentration of the lysates was measured using a Bio-Rad protein assay kit (Hercules, CA, USA). Mouse TNF-α and IL-1β protein was quantified using TNF-α and IL-1β ELISA kits (Biosource, Camarillo, CA, USA), respectively, according to the manufacturer's instructions.
Data are represented as mean ± SEM. The statistical significance of differences was analyzed using the PASW statistical program (SPSS Inc., Chicago, IL, USA). Statistical analyses were performed using the Student's t test or one-way or two-way ANOVA followed by Tukey's post hoc tests. A p value less than 0.05 was considered to be statistically significant.
This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2008-0062413, 2009-0081467, and 2010-0026575).
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