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Chemokine CXCL13–CXCR5 signaling in neuroinflammation and pathogenesis of chronic pain and neurological diseases

Cellular & Molecular Biology Letters volume 29, Article number: 134 (2024) Cite this article

Abstract

Chronic pain dramatically affects life qualities of the sufferers. It has posed a heavy burden to both patients and the health care system. However, the current treatments for chronic pain are usually insufficient and cause many unwanted side effects. Chemokine C–X–C motif ligand 13 (CXCL13), formerly recognized as a B cell chemokine, binds with the cognate receptor CXCR5, a G-protein-coupled receptor (GPCR), to participate in immune cell recruitments and immune modulations. Recent studies further demonstrated that CXCL13–CXCR5 signaling is implicated in chronic pain via promoting neuroimmune interaction and neuroinflammation in the sensory system. In addition, some latest work also pointed out the involvement of CXCL13–CXCR5 in the pathogenesis of certain neurological diseases, including ischemic stroke and amyotrophic lateral sclerosis. Therefore, we aim to outline the recent findings in regard to the involvement of CXCL13–CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling contributes to the pathogenesis of these neurological diseases via regulating neuroimmune interaction and neuroinflammation. Strategies that can specifically target CXCL13–CXCR5 signaling in distinct locations may provide new therapeutic options for these neurological diseases.

Introduction

Chronic pain is a debilitating condition that dramatically affects the life quality of suffering patients. According to epidemiology estimation, around 20% of the world’s population are suffering from chronic pain [1]. Chronic pain oftentimes lasts over months or even years that causes great amount of health cost and poses heavy financial burden to both the patients and the society [2]. Even worse, people who suffer from chronic pain are more prone to develop negative emotions, including anxiety, depression, and loss of motivation [3, 4]. Severe and long-lasting pain can even trigger suicidal tendencies among the sufferers [5]. Thus, chronic pain tortures the sufferers both physically and mentally. However, current treatment regimen for chronic pain, including nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and antidepressants, are usually insufficient and can cause certain adverse effects, including gastric ulcer, kidney damage, and addiction [6,7,8]. Therefore, to improve chronic pain management and reduce side effects, it is better to understand the mechanisms underlying chronic pain and identify novel therapeutic targets.

The immune system works together with the nervous system to contribute to neuroinflammation [9]. The neuroimmune interaction incorporates a number of signaling and types of cells, which include neurons, glia, immune cells, and other non-neuronal cells [8, 9]. It has become more and more evident that neuroinflammation plays a critical role in mediating and sustaining chronic pain and neurodegenerative diseases [10,11,12,13,14,15]. Neuroinflammation, which is mainly triggered by oxidative stress, inflammatory mediators, proinflammatory cytokines, or chemokines, can take place in local inflamed tissues, peripheral sensory nerves, spinal cord, or the brain during chronic pain [16,17,18,19,20,21,22,23]. Glial or immune cells contribute to neuroinflammation via releasing proinflammatory cytokines or chemokines [24, 25]. Conversely, these proinflammatory substances are produced from nerve endings and sensory neurons as well to trigger glia activation and immune cell infiltration [26]. Chemokines play an important role in the immune system by exerting chemotactic effect [27]. Recent evidence indicates a critical role of chemokine chemokine C–X–C motif ligand (CXCL)13–CXCR5 signaling in chronic pain and certain neurological diseases via mediating neuro-immune interaction and triggering neuroinflammation.

Overview of CXCL13–CXCR5 signaling

The chemokine CXCL13 was initially termed as B lymphocyte chemoattractant (BLC) or B cell attracting chemokine 1 (BCA-1) due to the fact that it was the first chemokine found to exert selective chemotaxis on B cells [28, 29]. While CXCL13 is mainly chemotactic for B cell, it also attracts certain subtypes of T cells as well as macrophages [28, 30]. CXCL13 has been found to be constitutively expressed in B cell-rich follicles of the secondary lymphoid organs, including spleen and lymph nodes. [31]. CXCR5, a G-protein-coupled receptor (GPCR), which was once known as Burkitt’s lymphoma receptor 1 (BLR1), is the only receptor identified for CXCL13 so far. It is mainly distributed in B cells and shows expression in a subtype of CD4+ T cells and dendritic cells as well [31, 32]. CXCL13 binds with CXCR5 to produce chemotaxis or modulate cellular function of these types of cells to contribute to physiological functions including lymphoid neogenesis, lymphoid organization, and immune responses [33]. In addition to the expression on certain immune cells, emerging evidence also demonstrates that the peripheral and central nervous system has functional CXCR5 expression, including neurons and astrocytes [34, 35]. These findings, thus, provide a cellular basis for CXCL13–CXCL5 signaling to regulate chronic pain or neurological diseases via neuroimmune interaction. Under certain chronic pain and neurological disease conditions, CXCL13–CXCR5 expression or downstream signaling in the nervous system can be dysregulated, thus contributing to the pathogenesis of these diseases.

The intracellular signaling conveyed by CXCR5 is in accordance with classical GPCR activation mechanism, which consequently activates a number of intracellular signaling molecules, including nuclear factor-κB (NF-κB), protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (p38 MAPK) (Fig. 1) [33]. It should be noted that the exact downstream signaling conveyed by CXCL13–CXCR5 may depend on types of cells and distinct physiology or pathophysiology conditions. After tissue inflammation or nerve injury occurs, the activation of these intracellular signaling conveyed through CXCL13–CXCR5, including NF-κB, ERK, and p38 MAPK, results in proinflammatory cytokine production that contributes to neuroimmune interaction and neuroinflammation, which is important for the development and maintenance of chronic pain (Fig. 1) [34, 36]. Moreover, CXCL13–CXCR5-mediated p38 MAPK activation can promote Nav1.8 channel activity, resulting in hyperexcitability of nociceptive sensory neurons (Fig. 1) [37]. Here, in this review, we aim to outline the recent findings in regard to the involvement of CXCL13–CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling regulates neuroimmune interaction and neuroinflammation to contribute to pathogenesis of these diseases.

Fig. 1
figure 1

Intracellular signaling pathways conveyed by CXCL13–CXCR5. Under specific physiological or pathophysiological conditions, CXCL13 is released and acts on its receptor CXCR5, a GPCR, to activate distinct downstream signaling. These signaling pathways contribute to physiological functions or pathophysiological conditions including growth/proliferation, invasion, gene transcription, and migration. When tissue inflammation or nerve injury occurs, CXCL13–CXCR5-mediated gene transcription produces proinflammatory cytokines, including IL-1β, tumor necrosis factor (TNF), and IL-6, that are released into extracellular space. These cytokines can activate neurons or cause microglial activation via a neuroimmune interaction, contributing to the development and maintenance of chronic pain [34,35,36]. p38 MAPK activation promotes Nav1.8 channel activity in nociceptive neurons, resulting in neuron hyperexcitability and pain [37]. The schematic picture was created with BioRender

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CXCL13 signaling in chronic pain

CXCL13 in spinal nerve ligation (SNL)-induced neuropathic pain and affective disorder

The pioneering work from Jiang et al. identified a significant upregulation of CXCL13 expression in spinal cord dorsal horn (SCDH) in SNL model mice [35]. Immunostaining further identified that CXCL13 was mainly expressed by spinal neurons, whereas CXCR5 showed expression exclusively in spinal astrocytes and only partially in neurons in SNL model mice (Fig. 2, Table 1) [35]. Cxcl13 gene knockdown in spinal cord attenuated neuropathic pain in SNL model mice [35]. The authors further identified a suppressive effect conducted by miR-186-5p, a microRNA colocalized with CXCL13, on CXCL13 expression in spinal neurons. Employing Cxcr5 gene knockout strategy or conducting Cxcr5 gene knockdown in spinal cord both ameliorated neuropathic pain of model mice [35]. Upon release from neurons, CXCL13 acted on astrocytic CXCR5 to trigger ERK-dependent astrocyte activation, resulting in the release of proinflammatory cytokines. These substances either directly acted on spinal neurons or cause microglia activation to augment and maintain pain signal transduction [38]. Thus, this work is the first study to demonstrate the contribution of CXCL13–CXCR5 signaling to chronic pain via mediating spinal neuron-astrocyte crosstalk, which paved the way for subsequent related studies. Targeting CXCL13 via inducing miR-186-5p expression or blocking CXCR5 in spinal cord may be a potential therapeutic option for neuropathic pain management.

Fig. 2
figure 2

Summary of the neuroimmune interaction mediated via CXCL13–CXCR5 signaling in the nervous system during chronic pain and neurological diseases. In the periphery (joint), during RA, CXCL13 activates ERK and p38 MAPK via CXCR5 to promote TNF production in MH7A cells, which may contribute to joint inflammation and pain in RA [89]. In dorsal root ganglia (DRG) and TG, during chronic pain, CXCL13 is produced from sensory neurons and activates CXCR5 expressed by sensory neurons via an autocrine manner [36, 37]. CXCR5 activation promotes TNF and IL-1β production in sensory neurons and enhances Nav1.8 channel activity via p38 MAPK to promote nociceptive neuron hyperexcitability [36, 37]. In SCDH, during chronic pain, CXCL13 is produced from spinal neurons. On one hand, CXCL13 acts on CXCR5 expressed by astrocytes to promote astrocyte activation, resulting in proinflammatory cytokine production, such as CCL2 and CCL7 [35]. On the other hand, CXCL13 activates CXCR5 expressed by neurons via an autocrine manner to promote IL-6 production [34]. These cytokines either directly activate spinal neurons or cause microglial activation to augment and maintain chronic pain condition. Conversely, in spinal cord ventral horn (SCVH), CXCL13 is produced from spinal motor neurons and acts on CXCR5 expressed by motor neurons via an autocrine manner to exert protective effects on motor neuron loss by ameliorating astrocytosis and microgliosis during amyotrophic lateral sclerosis (ALS) [104]. In anterior cingulate cortex (ACC), during chronic pain, CXCL13 and CXCR5 are both expressed in neurons. CXCL13 increases spontaneous excitatory postsynaptic currents (sEPSCs) in ACC and CXCR5 contributes to the increases in glutamatergic synaptic transmission [44]. In ipsilateral hemisphere, during ischemic stroke, CXCL13 is expressed on the inflamed cerebral vessels and recruits IL-21-producing T follicular helper (TFH) cells via activating CXCR5 expressed by these cells. IL-21 released from infiltrated TFH cells then activates interleukin-21 receptor (IL-21R) expressed on neurons to trigger neuronal death via Janus kinase (JAK)/STAT signaling [107]. The schematic picture was created with BioRender

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Table 1 Summary of cellular distribution of CXCL13–CXCR5 in different models of pain or neurological diseases
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Gene expression change and its modulation in sensory ganglia, such as dorsal root ganglia (DRG), plays an important role in the development of neuropathic pain conditions [7]. Epigenetic mechanisms have been increasingly reported to contribute to chronic pain modulation [39]. Recently, Ma et al. reported an epigenetic modulatory mechanism of CXCL13’s production from DRG neurons of SNL-induced neuropathic pain model mice [40]. The authors found that the expression of a transcription factor called zinc finger protein 382 (ZNF382) was persistently downregulated in the injured DRG neurons following SNL model establishment. The downregulation of ZNF382 resulted in its loss of binding with the silencer located in the distal upstream of Cxcl13 gene promoter, which weakened the inhibitory effect from epigenetic modification of Cxcl13 gene promoter via reducing transcriptional silencing complex formation. This epigenetic modulatory mechanism, in turn, resulted in transcriptional activation of the Cxcl13 gene in injured DRG neurons and subsequent production of the CXCL13 protein. CXCL13 released from injured DRG neurons conversely acted upon CXCR5 expressed in DRG neurons per se via an autocrine manner to further promote ERK-dependent production of inflammatory mediators, resulting in chronic pain [40]. Thus, epigenetic modification of Cxcl13 gene expression in peripheral sensory neurons represents a novel mechanism underlying chronic neuropathic pain.

Patients with chronic neuropathic pain usually develop emotional disorders, including aversion, depression, and anxiety, that dramatically affect life quality [41]. Up to date, there is mounting evidence suggesting an important contribution of the anterior cingulate cortex (ACC) in the brain to pain-related negative emotions [42, 43]. The work by Wu et al. found that the expression of CXCL13–CXCR5 in ACC was remarkably upregulated in SNL model mice [44]. CXCL13 and CXCR5 were predominantly expressed in neurons of ACC (Fig. 2, Table 1). The SNL model mice displayed obvious pain-related aversive behavior, which was significantly improved by Cxcr5 gene knockdown in ACC. Electrophysiology recording further revealed that CXCL13 perfusion increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs) in ACC slices, whereas Cxcr5 knockdown reduced glutamatergic synaptic transmission increases in ACC slices of SNL model mice. Therefore, this work demonstrates that the increase in CXCL13–CXCR5 expression in ACC is involved in neuropathic pain-associated aversive behavior.

CXCL13 in painful diabetic neuropathy

Painful diabetic neuropathy (PDN) is a common neurological symptom accompanying patients with diabetes mellitus [45]. PDN is characterized with stinging/burning sensation, numbness, and or loss of sensation at the distal end of the lower extremities, imposing heavy burdens on patients’ life quality [46]. However, some currently approved medications for PDN management, including tricyclic antidepressants, serotonin, and norepinephrine reuptake inhibitors or anticonvulsants, cannot produce sufficient relieving effects on patients, rendering it a quite challenging neurological condition in clinic [47]. Therefore, it is of great interest to identify new targets for PDN.

Recently, Liu et al. identified a critical role of spinal CXCL13–CXCR5 signaling in mediating PDN in a mouse model of type 2 diabetes [48]. This group utilized db/db (leptin receptor mutant) strain mice that exhibit hyperglycemia, obesity, and persistent mechanical pain hypersensitivity similar with human type 2 diabetes [49]. They found that CXCL13–CXCR5 expression in spinal cord was significantly upregulated in db/db mice. Immunofluorescence indicated CXCL13 was exclusively located on spinal neurons, whereas CXCR5 was predominantly distributed on spinal astrocytes, with few expression on spinal neurons or microglia (Fig. 2, Table 1), a result similar with the previous study [35]. ERK, AKT, and signal transducer and activator of transcription 3 (STAT3) are important signaling molecules involved in neuroinflammation, and their activation by phosphorylation is highly correlated with central sensitization [50,51,52]. The authors found db/db mice showed increased expression of p-ERK, p-AKT, and p-STAT3, as well as glial cell activation, in the spinal cord. Pharmacological blocking of ERK and STAT signaling attenuated mechanical allodynia of db/db mice. Intrathecal CXCL13 injection to naive mice triggered mechanical allodynia as well as an upregulation of p-ERK, p-AKT, and p-STAT3 expression in spinal cord. These effects were all abolished in mice deficient in Cxcr5 (Cxcr5−/−). Finally, knocking down Cxcr5 gene in spinal cord attenuated mechanical allodynia of db/db mice [48]. Thus, this study reveals an important contribution of spinal CXCL13–CXCR5 signaling to mechanical allodynia of diabetic model mice. The exact downstream signaling of CXCL13–CXCR5 that leads to spinal glial cell overactivation and pain hypersensitivity of diabetes model mice is still awaiting further investigation.

CXCL13 in complex regional pain syndrome type I

Complex regional pain syndrome type I (CRPS-I) oftentimes occurs secondary to an initial injury, including surgery, fracture, and ischemia. It usually involves the patient’s extremities and may spread to other body regions [53, 54]. CRPS-I can cause severe and long-lasting pain that affects the patients [55]. However, conventional treatments, e.g., steroids or NSAIDs, do not produce desirable relieving effects on CRPS-I [56]..

To facilitate mechanism investigation of CRPS-I, the chronic postischemic pain (CPIP) model, which recapitulates several key pathological features of human CRPS-I, was developed to mimic CRPS-I [57,58,59]. By means of this animal model of CRPS-I, our recent work identified a critical contribution of spinal CXCL13–CXCR5 signaling to both mechanical and cold allodynia via autocrine mechanism in model mice [34]. Work from us and others have revealed that spinal neuroinflammation plays a critical role in mediating glial cell overactivation, central sensitization, and pain hypersensitivity in CRPS-I model animals [8, 60,61,62,63]. To further screen potential molecules or signaling involved in spinal neuroinflammation, we employed RNA sequencing (RNA-seq) to look for possible candidates in ipsilateral spinal cord dorsal horn (SCDH) of CPIP model rats. Our work identified the CXCL13 gene among the most upregulated genes in CPIP model rats [64]. The expression of CXCL13 and CXCR5 was further confirmed to be upregulated in ipsilateral SCDH using a mouse model of CPIP [34]. CXCL13 and CXCR5 were predominantly expressed in spinal neurons of CPIP model mice (Fig. 2, Table 1). Neutralizing spinal CXCL13 or genetic deletion of Cxcr5 (Cxcr5−/−) reduced mechanical/cold allodynia, as well as spinal glial cell overactivation and c-Fos activation in SCDH of CPIP model mice, demonstrating an important role of CXCL13–CXCR5 signaling in mediating pain response of model mice [34]. It is known that patients with CRPS-I can develop emotional disorders owing to chronic pain [65]. Our work further examined the emotional disorders of CPIP model mice and found that CPIP model mice exhibited aversive behavior, an indication of emotional disorders similar with patients with CRPS-I. Interestingly, the aversive behavior was significantly reduced in Cxcr5−/− mice [34]. The involvement of sexual dimorphism in chronic pain mechanisms has been widely acknowledged [66, 67]. Our work also tested female mice and found that female Cxcr5−/− mice showed similar improvement in mechanical allodynia compared with male mice. This result, thus, rules out the possible involvement of sexual dimorphism in CXCL13–CXCR5 signaling in CPIP model mice [34].

In this work, the upstream signaling related to CXCL13 overexpression was further explored and was found to be mediated by STAT3 signaling in spinal cord neurons, whereas CXCR5 was coupled to downstream NF-κB signaling and triggered proinflammatory cytokine IL-6 production from spinal cord neurons [34]. Previous work identified that IL-6 receptor (IL-6R) is predominantly expressed on microglia in spinal cord [68]. Thus, IL-6 produced by spinal neurons may in turn activate microglial IL-6R to promote microgliosis and initiate neuron–glia crosstalk that contributes to central sensitization and pain development as reported in previous work [68, 69]. Future work that can target IL-6 production specifically in spinal neurons is desirable to further support the role of neuronal IL-6 in mediating mechanical allodynia of CPIP model mice. Finally, in this work, targeted overexpression of CXCL13 in spinal cord dorsal horn neurons via a neuron-specific promoter is enough to trigger persistent mechanical allodynia in naive mice [34]. Therefore, this work reveals that neuronal CXCL13–CXCR5 signaling, via autocrine manner, contributes to mechanical and cold pain hypersensitivity in a mouse model of CRPS-I. Targeting the spinal CXCL13–CXCR5 pathway may present a novel therapeutic approach for CRPS-I management.

One particular interesting finding of this work is that CXCR5 expression was found to be exclusively upregulated in spinal neurons of CPIP model mice [34]. In contrast, two aforementioned studies revealed CXCR5 is predominantly upregulated in spinal astrocytes, instead of neurons, in spinal nerve ligation (SNL) model and PDN model mice, respectively [35, 48]. Therefore, it is likely that CXCR5 expression in spinal cord can be triggered in different types of cells under specific pathological pain conditions, which is worth of further investigation.

CXCL13 in chronic constriction injury-induced neuropathic pain

Using an animal model of chronic constriction injury (CCI)-induced neuropathic pain model, one study identified a significant upregulation of CXCL13 and CXCR5 expression in the spinal cord of model animals [70]. The study further identified an important regulatory effect of transcription factor interferon regulatory factor 5 (IRF5) on CXCL13 expression in spinal cord. IRF5 is critically involved in both innate and adaptive immunity via conducting signals downstream of Toll-like receptors [71]. The authors found that IRF5 was overexpressed in spinal cord of CCI model rats, and it directly and specifically bound to the Cxcl13 gene promoter, thus facilitating Cxcl13 gene overexpression during chronic pain. Irf5 gene knockdown reduced CXCL13 overexpression and alleviated neuropathic pain-like behavior in CCI model rats. It is, thus, proposed that upregulated IRF5 promotes CXCL13 overexpression in spinal cord, contributing to CCI-induced neuropathic pain [70]. CXCL13 may further be transported from the injured site to spinal cord or DRG via axonal transport, where it binds to the upregulated CXCR5 and mediates CCI-induced neuropathic pain [72]. In addition to peripheral sensory system and spinal cord, RNA-seq revealed Cxcl13 gene expression was also significantly upregulated in the ACC of CCI model rats [73], a finding similar with results derived from SNL model animals [44]. This finding implicates a possible involvement of CXCL13 in mediating pain-related negative emotions of CCI model mice. Thus, further studies will be needed to validate this hypothesis.

CXCL13 in orofacial neuropathic pain

Chronic neuropathic pain of orofacial region resulting from nerve trauma, compression, or demyelination is a debilitating pain condition and oftentimes refractory to treatments [74, 75]. Trigeminal ganglion (TG) is a crucial site for pain transmission and pain modulation from the peripheral to the central nervous system in the oral maxillofacial region. Partial infraorbital nerve ligation (pIONL) model is a commonly utilized animal model for the study of orofacial pain [76]. With the aid of this animal model, Zhang et al. reported a considerable increase in the expression of both CXCL13 and CXCR5 in TG of pIONL model mice [36]. Immunostaining revealed that CXCL13 and CXCR5 were both expressed in neurons of TG of pIONL model mice (Fig. 2, Table 1). The knockdown of the Cxcl13 gene in TG before or after pIONL led to a notable decrease in mechanical hypersensitivity in model mice, indicating a critical role of CXCL13 in both development and maintenance phase of orofacial neuropathic pain [36]. Additionally, Cxcr5−/− mice and Cxcr5 gene knockdown mice showed significantly improved mechanical pain hypersensitivity after pIONL [36, 77]. The activation of CXCR5 results in ERK- and p38 MAPK-dependent proinflammatory cytokines (TNF and IL-1β) production in TG. Pharmacological blocking of ERK or p38 MAPK attenuates orofacial neuropathic pain in pIONL model animals [36, 77]. Thus, targeting CXCL13–CXCR5 and its downstream ERK or p38 MAPK signaling in TG may represent novel therapeutic approaches for orofacial neuropathic pain management.

CXCL13 in complete Freund’s adjuvant-induced inflammatory pain

Complete Freund’s adjuvant (CFA) is a water-in-oil emulsion containing heat-killed mycobacteria [78]. The administration of CFA causes a series of inflammatory reactions, including macrophage activation and a massive infiltration of neutrophils [79]. Activated macrophages and neutrophils continually release large amounts of ROS and proinflammatory cytokines including TNF, IL-1β, and IL-6 that activate or sensitize peripheral nerve endings to trigger persistent pain [79]. Thus, the injection of CFA in animal footpad or joint represent well-established animal models for studying inflammatory pain. In a mouse model of CFA-induced inflammatory pain, Wu et al. identified a significant upregulation of the expression of CXCL13 as well as its receptor CXCR5 in ipsilateral DRG of model mice [37]. They further found that CXCL13 is broadly expressed in DRG neurons, whereas CXCR5 showed predominant expression in small-to-medium-sized DRG neurons after CFA treatment. Cxcr5−/− mice exhibited a substantial improvement in both heat hyperalgesia and mechanical allodynia compared with wild-type mice after CFA treatment. To further investigate the mechanisms underlying how CXCR5 contributes to pain hypersensitivity of CFA model mice, the authors performed electrophysiology recording and found that the deletion of the Cxcr5 gene reduced the enhancement in neuronal excitability of DRG neurons triggered by either CFA treatment or CXCL13 incubation, suggesting CXCR5’s involvement in modulating neuronal excitability [37]. Immunostaining uncovered a colocalization of Nav1.8, a sodium channel crucial for the induction of action potentials in nociceptive neurons, with CXCR5 in DRG neurons. Incubating neurons with CXCL13 dose dependently increased peak current density of Nav1.8 channel in DRG neurons via a CXCR5-dependent mechanism. It is known that Nav1.8 in DRG neurons can be phosphorylated by p38 MAPK, resulting in an increase in the current density in sensory neurons [80]. Therefore, the authors examined whether CFA treatment and CXCL13 can promote p38 MAPK activation in DRG neurons. They found that CFA and CXCL13 can both trigger p38 MAPK phosphorylation in DRG of WT mice but not in Cxcr5−/− mice. Pharmacological blocking of p38 MAPK attenuates CXCL13-induced upregulation in Nav1.8 channel current density in DRG neurons, as well as mechanical and heat pain hypersensitivity, in CFA model mice [37]. Therefore, this study indicates that, upon tissue inflammation, DRG neuron-derived CXCL13 activates neuronal CXCR5 via an autocrine manner to enhance Nav1.8 channel activity in DRG neurons through p38-dependent mechanism, all of which contributes to peripheral sensitization and chronic inflammatory pain. Targeting peripheral CXCL13–CXCL5 signaling may be a potential method for ameliorating inflammatory pain.

CXCL3 in rheumatoid arthritis (RA)

RA is a chronic and autoimmune disorder, inflaming and damaging the joints as well as other body parts, including the lung, heart, and eyes [81, 82]. The joint inflammation can cause chronic pain and ultimately lead to bone erosion, joint deformity, and even disability in patients [81]. The persistent joint pain is usually the most complained symptom among patients with RA [83].

TNF is considered as a key inflammatory cytokine involved in RA pathogenesis and progression [84]. TNF neutralizing biologics have been used in clinic to treat RA and reduce joint pain [84]. Studies reveal that TNF can activate tumor necrosis factor receptor (TNFR)1 on DRG neurons to potentiate TTX-resistant Na+ channels, thus promoting pain and peripheral sensitization [85, 86]. Additionally, TNF also activates TNFR2 on macrophages to facilitate macrophage accumulation in the DRG, resulting in neuroinflammation [85]. These two processes contribute to joint pain mechanisms in RA together. Accordingly, understanding how TNF is produced during RA is critical for identifying targets for RA inflammation and pain management.

CXCL13 has been found to be a potential biomarker for RA severity and is related with joint inflammation [87, 88]. In one recent study, it was found that CXCL13 incubation can trigger TNF production from the MH7A cell line that resembles human RA synovial fibroblasts [89]. CXCR5 expression was found to be significantly increased in synovial tissue of a mouse model of RA. CXCL13, via CXCR5, activates the downstream ERK and p38 signaling to promote TNF production in MH7A cells. The knockdown of the Cxcl13 gene reduces TNF expression as well as joint inflammation in RA model mice [89]. It will be interesting to continue to examine whether joint pain is also ameliorated by Cxcl13 gene knockdown. This work demonstrates an involvement of CXCL13–CXCR5 signaling in RA via promoting TNF production from synovial fibroblasts. Blocking CXCL13–CXCR5 signaling may provide therapeutic potentials to alleviate joint inflammation and pain in RA.

CXCL13 in chronic postsurgical pain

Chronic postsurgical pain (CPSP) is among the most common complications for patients after a major surgery [90, 91]. It is estimated that 10–30% of patients complain prolonged pain 1 year after the surgery [91]. In a recent study, Yi et al. established a skin/muscle incision and retraction (SMIR) rat model to mimic CPSP and found that the expression of CXCL13 and CXCR5 was significantly increased in spinal cord tissues of model animals [92]. Intrathecal application of CXCL13 neutralizing antibody ameliorated SMIR-induced mechanical hyperalgesia and reduced nod-like receptor protein 3 (NLRP3) inflammasome activation, proinflammatory cytokine production (IL-1β and IL-18) as well as astrocyte overactivation in spinal cord of SMIR model rats. Furthermore, applying recombinant CXCL13 protein promoted the activation of NLRP3 inflammasome and the related inflammatory responses in primary rat astrocytes and increased glial fibrillary acidic protein (GFAP) expression in a dose-dependent manner. These effects were partially reversed by the application of INF39, a specific NLRP3 inflammasome inhibitor [93]. This study suggests that CXCL13–CXCR5 may promote neuroinflammation and chronic pain via activating NLRP3 inflammasome-dependent signaling in spinal cord of CPSP model animals. But it still remains to be further investigated how CXCR5 is exactly coupled with downstream NLRP3 inflammasome signaling under a CPSP condition.

CXCL13 in bone cancer pain

Patients develop bone cancer pain (BCP) with primary bone cancer or secondary bone metastasis from distant sites, e.g., lung, prostate, and breast.[94]. BCP produces severe pain that dramatically affects the patients’ life quality. However, a majority of patients suffering from BCP usually receive insufficient pain management due to the relative limited analgesic effects and the adverse reactions of conventional therapeutics [95]. In terms of mechanisms, BCP is usually taken as a distinct type of pain with both overlapping and different characters of inflammatory and neuropathic pain [94, 96].

The contribution of spinal CXCL13–CXCR5 signaling to BCP has recently been reported [97]. BCP was established in rats via inoculating Walker 256 carcinoma cells in the tibia cavity. The expression of CXCL13 and CXCR5 was found to be increased in the spinal cord of model rats [97, 98]. The mechanical allodynia manifested by the BCP model rats were significantly alleviated by Cxcr5 gene knockdown in spinal cord. Moreover, spinal injection of CXCL13 induced an increase in p-p38, p-ERK, and p-AKT expression in the spinal cord of BCP model rats, which was inhibited by spinal Cxcr5 gene knockdown. This result indicates that CXCL13 may act upon CXCR5 to activate downstream p38, ERK, and AKT signaling to mediate BCP. However, the exact contribution of these downstream signaling pathway of CXCR5 to the pain hypersensitivity of BCP model animals still needs further investigation. Another study investigated the upstream regulatory mechanism of CXCL13 and found that lncRNA NONRATT009773.2 modulates CXCL13 expression by functioning as a microRNA sponge to absorb miR-708-5p in spinal cord of BCP model rats [98]. The upregulated CXCL13 may further induce neuroinflammation, including astrocyte overactivation and proinflammatory cytokine production in the spinal cord. In all, these studies suggest an involvement of spinal CXCL13–CXCR5 signaling in mediating BCP.

CXCL13 in remifentanil-induced hyperalgesia

The chronic usage of opioids adversely induces pain, a phenomenon called opioid-induced hyperalgesia. Remifentanil is a short-acting opioid agonist with a lower risk of respiratory depression and delayed awakening after withdrawal. However, as an opioid, the usage of remifentanil is still limited by the occurrence of opioid-induced hyperalgesia [99]. Therefore, identifying mechanisms underlying remifentanil-induced hyperalgesia (RIH) is of clinical significance.

One study found that CXCL13–CXCR5 expression in the rat spinal dorsal horn was significantly increased after remifentanil intervention [100]. Intrathecal injection of CXCL13 neutralizing antibody dose dependently improved mechanical and thermal hyperalgesia in RIH model rats. To further explore how spinal CXCL13 contributes to RIH, the author focused on interleukin-17 receptor (IL-17)/interleukin-17 receptor A (IL-17RA) signaling. They found that the expression of IL-17 and its receptor IL-17RA in spinal dorsal horn of rats was also increased significantly following remifentanil intervention [100]. Spinal IL-17/IL-17RA signaling has been implicated in chronic pain [101]. IL-17/IL-17RA contributes to chemotherapy-induced peripheral neuropathy via mediating neuron-glial crosstalk and promoting neuron hyperexcitability in the spinal cord [102]. The authors found that CXCL13 neutralizing antibody inhibited the overexpression of IL-17/IL-17RA as well as the trafficking of GluN2B-containing NMDA receptor to the cell membrane. Furthermore, blocking spinal IL-17 reduced the trafficking of GluN2B-containing NMDA receptor from the cytosol to the membrane and reduced RIH in model rats [100]. Although the detailed mechanisms underlying how CXCL13 modulates IL-17/IL-17RA and GluN2B expression in RIH remains unknown, this finding demonstrates an important role of spinal CXCL13 in RIH via IL-17/IL-17RA-mediated GluN2B trafficking to the cell membrane. Therefore, spinal CXCL13 signaling may be a potential target for RIH management.

CXCL13 signaling in neurological diseases

CXCL13 in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration that leads to muscle weakness, paralysis, respiratory insufficiency, and ultimate death [103]. Huge efforts have been devoted to identify potential therapeutic targets for slowing or preventing ALS’s progression. Recently, one study proposed the CXCL13–CXCR5 axis may be involved in ALS using both in vitro and in vivo experiments on ALS model mice and tissue samples from patients with ALS [104]. Using a mouse model that mimics ALS, the group found Cxcl13 and Cxcr5 gene expression was progressively upregulated in lumbar spinal cord of a fast progressing ALS model mice. Immunostaining revealed that CXCL13 was expressed by motor neurons and partially by microglial cells, whereas CXCR5 was exclusively expressed in motor neurons in the spinal cord of ALS model mice (Fig. 2, Table 1). CXCL13 was also detected to be progressively and remarkably released into cerebrospinal fluid (CSF) of the fast progressing ALS model mice. Moreover, the group identified a marked upregulation of CXCL13 associated with motor neurons and the surrounding axons as well as in efferent motor axons in the ventral portion of spinal cord of ALS model mice, indicating that CXCL13 was further transferred to the periphery axons after ALS. Intraventricular neutralization of CXCL13 accelerated motor functional impairment and reduced survival of ALS model mice. Pathology examination further revealed that motor neuron damage, astrocyte hyperplasia as well as denervation atrophy of hind limb skeletal muscles of ALS model mice were aggravated by intraventricular CXCL13 neutralization [104].

To further explore how CXCL13 contributes to ALS pathogenesis, the group established a primary coculture system containing motor neurons, astrocytes, and microglia obtained from spinal cord of ALS model mouse embryos. Silencing of Cxcl13 expression exacerbated motor neuron loss and enhanced astrocytosis and microgliosis in the coculture system. Furthermore, the administration of recombinant CXCL13 protein to the coculture system under acute or chronic inflammatory condition protects motor neuron loss. The protective effect was abolished by CXCL13 neutralization. CXCL13 and CXCR5 were found to be upregulated in spinal motor neurons of patients with ALS, whereas CXCL13 levels in CSF of patients with ALS were lower than control subjects without neurological alterations [104]. The decreased CXCL13 level in CSF of patients with ALS is consistent with findings from the slow-progressing ALS model mice [104]. The authors interpreted that the lower CXCL13 levels in CSF might reflect motor neuron dysregulation in the spinal cord of both slow-progressing ALS model mice and patients with ALS. How this dysregulation in motor neuron occurs and how it affects CXCL13 release by motor neurons, however, still remain elusive. Thus, further studies will be needed to investigate this phenomenon in the slow-progressing ALS model mice and patients with ALS and its related mechanisms. Taken together, these data demonstrates an important role of CXCL13, expressed by spinal motor neurons, to reduce neuroinflammation and move alone motor axons to protect the degenerations in ALS model mice. The study implies that CXCL13 may be potentially used to ameliorate ALS. The study also indicates that the reduction in CXCL13 level in CSF of patients with ALS may possibly serve as a clinical indication for ALS progression (Table 2), although further clinical studies with more patients recruited are needed to validate this idea.

Table 2 Summary of the findings from clinical studies regarding CXCL13–CXCR5 expression dysregulation in pain or neurological diseases
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CXCL13 signaling in ischemic stroke

A majority of strokes are caused by artery occlusion that results in brain ischemia. When the initial occlusion resolves, the reperfusion of blood with proinflammatory cytokines and immune cells further causes secondary injury that is usually more damaging than the initial occlusion [105]. There are no clinically approved drugs targeting the inflammatory component of ischemic stroke. Exploring how immune cells infiltrate to ischemic brain and their role in neuron death may provide new targets for ischemic stroke management.

Previous work shows that a group of CD4+ T cell can produce IL-21 and contributes to damage following transient middle cerebral artery occlusion (tMCAO) in mice and patients with ischemic stroke [106]. One recent study continued to explore the mechanisms leading to the recruitment of this specific group of CD4+ T cells [107]. They identified a group of IL-21-producing CXCR5+CD4+ICOS-1+ T follicular helper (TFH) cells infiltrated to the ischemic brain of model mice. The administration of CXCL13-neutralizing antibody reduced TFH cells infiltration to the ischemic brain region and ameliorated ischemic injuries. Immunostaining revealed the presence of CD4+CXCR5+ T cells in ischemic brain regions and CXCL13+ vessels after ischemic injury in both model mice and human patients (Fig. 2, Table 1) [107]. The authors continued to look for the cellular distribution of IL-21 receptor, namely IL-21R, in the brain. They found that IL-21R was exclusively expressed in neurons, and its expression was upregulated during ischemic stroke in both mouse model and human patients (Fig. 2). This indicates a higher response can possibly be exerted by IL-21R-expressing neurons in response to IL-21 produced from infiltrated TFH cells during ischemic stroke. In vitro experiments further showed IL-21 activated JAK/STAT pathway to trigger caspase-mediated apoptosis in hypoxic neurons [107]. Therefore, this study uncovers an important role of CXCL13 expressed on inflamed cerebral vessels in recruiting IL-21-producing TFH cells via CXCR5 to produce neuroinflammation and subsequent neuronal death in ischemic stroke.

Conclusions and future perspectives

Here, in this review, we summarize the most recent achievements in the study of CXCL13–CXCR5 signaling in the nervous system. We focus on the biological function, cellular expression, signaling transduction of the CXCL13–CXCR5 axis, as well as the cellular interactions this axis mediates during pathogenesis of chronic pain, and certain neurological diseases. We also outline the current strategies that can specifically target the CXCL13–CXCR5 axis in chronic pain or neurological diseases (Table 3). In addition to the documents summarized as above, there are some other studies that have identify dysregulation in CXCL13–CXCR5 in an animal model of perioperative neurocognitive disorder and epilepsy in both animal model and human patients, as well as multiple sclerosis (MS), lyme neuroborreliosis (LNB), and anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDAR encephalitis) in human patients (Table 2) [108,109,110,111,112]. These studies in all may highlight an emerging importance of CXCL13 and CXCR5 as potential therapeutic targets or biomarkers for certain neurological diseases and brain inflammation.

Table 3 Strategies that can target or affect CXCL13–CXCR5 signaling for pain or neurological disease amelioration
Full size table

Although certain progress has been made in elucidating the contributions of CXCL13 signaling to chronic pain and certain neurological diseases, some research limitations still exist in this field that need further improvement in our view. First, the CXCL13–CXCR5 cellular expression patterns were exclusively derived from experiments with immunostaining. It is known that certain antibodies may lack validations of their specificities and the performance may not be consistent [113]. Therefore, the exact cellular distribution of CXCL13–CXCR5 in the nervous system needs to be further corroborated by means of some more reliable approaches, for example, in situ hybridization or the more advanced RNAscope technique. Second, it is apparent that CXCL13–CXCR5 exhibit expressions in both the immune and nervous systems. However, most of the current findings were derived from global Cxcr5 knockout animals or regional gene knockdown approaches. Conditional knockout of Cxcl13/Cxcr5 genes in specific types of cells or gene knockdown guided by tissue-specific promoter are still lacking. These techniques can help to unravel the precise involvement of CXCL13–CXCR5 signaling in specific cells or tissues in pathogenesis of chronic pain or neurological diseases. Third, there is emerging evidence demonstrating the presence of sexual dimorphism in mechanism of chronic pain [114,115,116]. It is known that chronic pain is usually more prevalent and more disabling in women than in men [117, 118]. However, most of the present findings indicating that CXCL13 signaling contributes to chronic pain are based upon experiments using male animals. Therefore, it is important to explore if CXCL13 signaling also contributes to chronic pain in female animals as well. If any human studies were performed to investigate the contribution of CXCL13–CXCR5 in chronic pain in the future, we suggest to discriminate between male and female human subjects. This can help to ascertain whether sexual dimorphism may exist in CXCL13 signaling in different chronic pain conditions.

Up to date, growing evidence has demonstrated the critical role of CXCL13–CXCR5 signaling in mediating neuroinflammation and the pathogenesis of chronic pain or certain neurological diseases. Strategies that can target CXCL13–CXCR5 signaling may provide new therapeutic options for these conditions.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

ACC:

Anterior cingulate cortex

Akt:

Protein kinase B

ALS:

Amyotrophic lateral sclerosis

BCA-1:

B cell attracting chemokine 1

BCP:

Bone cancer pain

BLC:

B lymphocyte chemoattractant

BLR1:

Burkitt’s lymphoma receptor 1

CCI:

Chronic constriction injury

CFA:

Complete Freund’s adjuvant

CPIP:

Chronic postischemic pain

CPSP:

Chronic postsurgical pain

CRPS-I:

Complex regional pain syndrome type I

CSF:

Cerebrospinal fluid

CXCL13:

Chemokine C–X–C motif ligand 13

CXCR5:

C–X–C chemokine receptor type 5

DRG:

Dorsal root ganglia

EPSCs:

Excitatory postsynaptic currents

ERK:

Extracellular signal-regulated kinase

GFAP:

Glial fibrillary acidic protein

GPCR:

G-protein-coupled receptor

IKK:

Inhibitor of kappa B kinase

IL-17RA:

Interleukin-17 receptor A

IL-21R:

Interleukin-21 receptor

IRF5:

Interferon regulatory factor 5

IκB:

Inhibitor of NF-κB

JAK:

Janus kinase

JNK:

C-Jun N-terminal kinase

LNB:

Lyme neuroborreliosis

MS:

Multiple sclerosis

NF-κB:

Nuclear factor-κB

NLRP3:

Nod-like receptor protein 3

NMDAR:

N-methyl-d-aspartate receptor

NSAIDs:

Nonsteroidal anti-inflammatory drugs

p38 MAPK:

p38 mitogen-activated protein kinase

PDN:

Painful diabetic neuropathy

PI3K:

Phosphatidylinositide 3-kinase

pIONL:

Partial infraorbital nerve ligation

RA:

Rheumatoid arthritis

RAS:

Rat sarcoma

RIH:

Remifentanil-induced hyperalgesia

SCDH:

Spinal cord dorsal horn

SCVH:

Spinal cord ventral horn

sEPSCs:

Spontaneous excitatory postsynaptic currents

SMIR:

Skin/muscle incision and retraction

SNL:

Spinal nerve ligation

STAT3:

Signal transducer and activator of transcription 3

TFH cells:

T follicular helper cells

TG:

Trigeminal ganglion

tMCAO:

Transient middle cerebral artery occlusion

TNFR:

Tumor necrosis factor receptor

TNF:

Tumor necrosis factor

ZNF382:

Zinc finger protein 382

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Acknowledgements

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Funding

This project was supported by National Natural Science Foundation of China (82474625 and 82305368), Zhejiang Provincial Natural Science Funds (LZ23H270001), and National High Level Traditional Chinese Medicine Hospital Clinical Research Funding (DZM-XZYY-23001).

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Author notes

  1. K.Z., M.C., and X.X. contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China

    Kaige Zheng, Muyan Chen, Xingjianyuan Xu, Peiyi Li, Chengyu Yin & Boyi Liu

  2. Department of Rehabilitation in Traditional Chinese Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Jie Wang

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Contributions

B.L. and J.W. defined the research topic. K.Z., M.C., and X.X. performed document retrieval, designed the figures, and wrote the first draft. P.L. and C.Y. designed the figures. M.C., K.Z., B.L., and J.W. prepared the final draft of the manuscript. All authors have read and approved the final draft of this manuscript.

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Zheng, K., Chen, M., Xu, X. et al. Chemokine CXCL13–CXCR5 signaling in neuroinflammation and pathogenesis of chronic pain and neurological diseases. Cell Mol Biol Lett 29, 134 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s11658-024-00653-y

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Keywords

Cellular & Molecular Biology Letters

ISSN: 1689-1392

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